Memory T cells has low activation threshold are characterized by their low activation threshold, strong effector function and resistance to conventional immunosuppressants. 1–10% of memory T cells generated through the recognition of peptides from commensal bacteria or environmental antigens can react to allogeneic major histocompatibility complex (MHC) molecules. Previous history of transplants, pregnancies, and blood transfusions confer alloantigen sensitization. Besides, homeostatic proliferation in a lymphopenic environment produce memory T cells that potentially impair tolerance induction to allografts. On the other hand, dialysis vintage and low serum levels of 25-OH-vitamin D in ESRD recipients correlates with the frequency of alloreactive memory T cells. Memory T cells divided into two major subsets with Central memory T cells express lymphoid homing markers CCR7 and CD62L, whereas effector memory T cells are CCR7−CD62L promote migration into peripheral cells. These T cell receptors and costimulatory signalling cascades enable memory T cells to respond to lower antigen threshold. Upon reactivation, memory CD4+ T cells become effector cells and activated the donor-reactive effector CD8+ T cells which contribute to the allograft rejection. Besides, the present of memory T cells pre transplantation has been associated with an increased risk for acute rejection among renal transplant recipients.
To overcome the consequence of alloreactive memory T cell in transplant rejection, the direct lymphoablation provide promising result in renal transplantation. Limiting CD4+ T helper signals during lymphoablation control the memory T cell expansion. Alefacept synergizes with CTLA4-Ig targeting alloreactive effector and memory T cells. Belatacept which is a second generation CTLA4-Ig prevent allograft rejection improve graft survival and reduce the side effect of CNI.
Meanwhile, reagents blocking LFA-1 (leukocyte function-associated antigen-1, an αLβ2 integrin) and VLA-4 (very late antigen-4, an α4β1 integrin) shown the ability to provide prolong allograft survival by prevent the early infiltration of endogenous donor-reactive memory CD8+ T cell into allograft.
In conclusion, memory T cells accelerate the risk of allograft rejection which compromise transplant tolerance. It is of great challenge for the diagnosis of T cell allosensitization among transplant recipients due to high heterogenicity of memory T cells. Besides, memory T cell shown variation of susceptibility to immunosuppressants. Further larger trial is needed for the development of novel approaches to control memory T cells and improve renal transplants survival.
Ramy Elshahat
2 years ago
Origin of alloreactive memory T cells:
Memory T cells are around 5-10% of all T cells. the source of these memory cells is an infection, exposure to environmental antigens, and in patients with ESRD some factors like exposure to dialysis & the low level of 25 OH-vitamin D. Location of memory T cells:
central memory T cells
Effector peripheral memory T cells circulating in the peripheral blood.
Terminally differentiated effector memory T cells (Temra)
TFh cells: beside B cell follicles and are essential for B cells responses and antibody generation.
Tissue-resident memory T cells (Trm): act as reservoirs in the tissues and do not circulate so, resistant to lymph-ablation
Why memory cells are important in renal transplantation
Not well-evaluated pre-transplant (crossmatch is only evaluating preformed antibodies)
lower activation threshold
persist for a long time when compared to naive cells
resistant to co-stimulation signals
resistant to regulatory T cells
not suppressed by conventional maintenance immunosuppressive drugs and also resistant to induction therapy Role in allograft rejection:
once memory CD4+ T cells get activated, they transform into effector t-cells rapidly & also activate CD8+ T cells and cause direct graft destruction. it also differentiates into THF and causes b-cell stimulation, DSA formation, and ABMR. Influence of memory T cells on allograft tolerance:
Under certain circumstances, memory T cells show a regulatory effect and suppress the immune response and there is concern regarding depleting lymphocyte induction may interfere with graft tolerance. Recent developments in targeting alloreactive T cell memory
Depleting induction: ATG, and Alemtuzumab both affect memory t-cell but Alemtuzumab has less effect.
costimulatory blockade (like belatacept): its CTLA4-Ig(inhibit signal II)unfortunately memory cells are more resistant to the effect of CTLA4-Ig.
Limiting trafficking of alloreactive memory T cells: like LFA-1 & VLA-4: in experiments, it prolongs allograft survival.
Nandita Sugumar
2 years ago
Summary
The memory T cells have 3 major identifying characteristics. These include the following :
Low activation threshold
Robust effector function
Resistance to conventional immunosuppression and costimulation blockade.
Alloreactive T cells can develop affinity by prior exposure to allogenic MHC molecules or by microbial infection. This poses a high risk for rejection.
They can originate from microbes or antigens presented by self MHC molecules. These can mimic allogenic MHC molecules. Thus, infection, blood transfusion, pregnancy, and previous transplants can all be a risk factor for rejection. Long dialysis period can be an additional risk factor for increased number of alloreactive memory T cells. This could be because of low serum 25-OH vitamin D.
There are 2 types of memory T cells :
Central
Effector
Heterologous immunity may or may not translate into worse transplant outcome. Memory T cells may be alloreactive and lead to graft rejection, but they have 1 major advantage :
They regulate inflammation
They suppress pro inflammatory immune response
Alloreactive memory T cell targeting therapy includes the following options :
Lymphoablation – antibody mediated deletion of lymphocytes done as part of induction therapy. It is useful in patients who are highly sensitized and in those who are receiving marginal grafts.
Co stimulators blockade – Tcm of less differentiated phenotype can be more sensitive to costimulatory blockade.
Diagnosing memory T cells will need tests that analyse cytokine production, follicular helper T cells. Peripheral blood samples need to be taken to identify memory T cells.
Manal Malik
3 years ago
Summary of Role of Memory T Cells in Allograft Rejection and ToleranceABMR is amajor cause of graft dysfunction ,the B cell is corner stone of interaction of immunological process(ABMR).
Route of Ag presention to Bcellsor B cells activating
1-intact soulable Ag through B cell receptor(BCR) enages intact Ag displayed on FDCs, Bcell or macrophage.
2-entering L.N through multiple routes depend on Ag size,presence of Ag Ab and complement,in addition to migratory DCs.
3-enteringwhite pulp spleen .the B cells is presenting the Ag to cells
small soulable protein< 14kd it direct activate B cells through FRC conduct (in L.N or spleen).
the DSA and poly reactive antibodies bind to soulable Antigens and activate complement receptor3(CR3,CD11b,CD18) so opsonized Antigens by B cells in follicles through complement receptor CD21(CR2) and CD35(CR1) or FCRY11B receptors.
Ags bound to macrophages and DCs in L.N these DCs and macrophages together with CD8 DCs,M2 metallephill macrophage and M2macrophage capture Ag viaSIGLECI,SIGNRI,TIR andc-type lectin and finally the Ag activate complement and they opsanized Ag delivers by CRI on FDS.
extracellular vesicular exosomes realease by allograft are capture by SIGN-RI M2 macrophage.FA180 then drain into L.N or spleen where presented DCs donor MHC delivered by exosomees to recipients DCs and stimulate CD8 Tcell via direct way.
glyco protien with salcilic acid capture by sialodhesion (CD 169) , the macrophage deliver exosome donor MHC to FDCS with Bcell zone.
early Bcells activate by non-antigen specific Bcells or specific antigen (BCR-bound Ag)and interact with antigen specific Tcell receptor on CD4 Tcell and recognize MHC of recipient so Tcell have indirect specificity for MHC molecule expressed by recipient Bcell so activate or differentiate recipient Bcell into PCS producing DSA. The activation of the Tcall require DCS that acquired antigen from allograft and migrate to lymphnode when DCS arrive in the tissue.
Large antigen such as capture particular vaccine antigen, pathogen and allograft-drived exosome and membrane fragment so DCS process and present capture antigen to Tcell inducing Tcell response more rapidly then independently migration DCS.
TCR signaling strength are unclear and their differentiation into Tfh also require specific signals drived from the TCR .
Bcell at the T/B interfere result in producing PCS,memory Bcells as Bcells.
the pre GC response generate PCs that lower affinity than post -GCPCs so importance of the pre GC response to DSA production following solid organ transplant and contribution of this response to AMR has not been delineated. Germinal center response
xtra follicular Bcells receive stimulation for follicularTfh cells.
ethey down regulate EB12.EB12 which realse Tcells. from out er follicule
in the absence of Tcell survival signals .Bcell undergo apoptosid in the light zone.
Belatacept inhibit Bcell and Tfh interaction so can control humeral response but still under under study.
Germinal centers responses to
consist of light and dark zone
the light zone contain FDCs and Tf.
dark zone is devoid FDCs.
Light zone B cells express CD86 and CD 38.
Bcells selected proliferate develop BCR specificity
some observation lead the author to suggest that TG-B production may be the mechanism by which Tfr inhibit B cell. Generation of memory Bcells and pcs..
plasma cell function is control of infection ,produce memory cel and protection against reinfection.
memory Bcells has 2 phases
1-early pre GC memory Bcells ,with lower affinity for IgM .
2- late phase post GC memoray Bcell with higher affinity and expressing IgM or IgG.
memory B cells generated in the pre GC and early GC peroid so pc later long lived
affinity and kinetics of memory B cell versus PC differentiation suggest that treatment of AMR and reduction of circulatory DSA may not prevent memory donor-specific B cell generation.
recent meeting 2017 by sensitization in transplantation Assessment of risk working group they mention that non existence of DSA does not equate to an absence of sensitization of memory B cells.
other explanation for humeral sensitization without DSA in Transplant recipeint include absorption of DSA by the allograft..
absence of clinical test of donor specificity memory B cells so STAR recommended the only patient without DSA and also without HLA sensitizing events such as pregnancy,blood transfusion and previous transplant ,implement should be consider immunological lower lower risk for alloimmune memory. Recall Bcell Respones
memory B cells differentiate into PCS by 2 ways
1-faster and high titre of antibody response,
2-higher affinity and class -switch PCs generate from GC B cells
IgG memory B cell predominate are IgM memory B cell in response of circulating antibodies.
factors affect rating of memory B cell up the Ag is depend on :
input , and type of memory B cell was generated and condition of Ag. Conclusion
de novo DSA is major cause of allo graft loss.
this review summarized the cellular process that generate an antibody response but not non Ab producing role of B cells.
insights into mechanism lead to Ab production and humeral memory from study of model Ags and how these process are altered by feature of organ transplant require further investigation.
failure of successful transplant influence by factors impact
1-on the cellular response that generate PCs .
2-quality of producing DSA.
3-the quality of memory donor specific B cells.
anew way to control DSA production while preserving protective immunity is a result of difference between immune response to moderate Ags pathogens and transplant antigens.
when initial Abs is producing these Abs bind to same epitopes driving thier production either selection of B cells with higher affinity than circulating Abs or in selection of B cell with specificity for new epitopes
response subset of CD4T cell that express the regulators T(treg) cell master regulator FOXP3 showing many phenotype characteristics of Tfh cells has .
ahmed saleeh
3 years ago
Memory Tcells
Benefits : rapid , strong effect on re-exposure to infections also in vaccinations and tumors .
Disadvantages : allograft rejection resistance to traditional immunosupression
*Origins of Alloreactive Memory T Cells :
•previous transplants, pregnancies, and blood transfusions.
•homeostatic proliferation in a lymphopenic environment
•end stage organ disease or treatment common in transplant candidates e.g vit D Defeciency
* memory T cells to respond to lower antigen doses with limited costimulation
this process is essential for host defense, it renders alloreactive memory T cells more dangerous in transplant
gamma interferon (IFNγ) secretion by memory helper T cells is required for de novo DSA generation
no indication that the presence of “heterologous immunity” in transplant recipients correlates with worse graft outcomes
ReCenT DeveLOPMenTS in TARgeTing ALLOReACTive T CeLL MeMORY
•Lymphoablation : ATG lymphoablation
•Costimulatory Blockade : second generation of CTLA4-Ig Belatacept
preventing memory T cell entrance into graft tissue should improve transplant outcome,the attempts to neutralize chemokines or chemokine receptors such as CCR5 or CXCR3 did not live up to the initial expectations
Nasrin Esfandiar
3 years ago
· Characteristics of memory cells include:
1-Low activation threshold
2-Potent effect or functions
3-Resistant to conventional immunosuppression
4-Resistant to co-stimulation blockade
They have an important role in alloreactive rejection.
Alloreactive memory T cells can be generated through heterologous immunity in mice previous transplants, pregnancy or blood transfusions are known route of alloimmune sensitization in human and could be developed by long exposure to dialysis low serum 25(OH)Vit. D is correlated with their frequency.
· Memory T cell subsets:
1-central memory T cell (T cm): express CCR7 and CD621
2-effecror memory T cell(Tem): CCR7 CD promote migration
3- Terminally differentiated effector memory T cell (Temra): CD45RA+ but CCR7- CD621- CD28 –
4-Tissue resident memory T cells (T rm): express CD69 αEβ7 integrin CD103.
They have an important role in protection against infections but facilate GVHD or rejection (related to donor and recipients, respectively).
5-T follicular helper (T fh): CD4+ CXR5 high3 important for B cell responses.
Memory T cell when reencounter to low antigen doses even with limited costimulation pathways activation such as CD28/CD80/CD86 and CD40 CD154, can activate rapidly.
This property is troublesome in transplantation.
Memory CD4+ T cell are resistant to common immunosuppression and result in DSA formation and ABMR. Therapeutic option is IFNγ inhibitors, neutralizing B cell activating factor and proliferation –inducing ligand.
Donor –reactive memory CD8+ T cell upregulates adhesion molecules and chemokines and result in leukocyte infiltration in to the graft.
In graft, memory CD8+ T cell proliferate and express ICOS and secrete IFNγ and result in in graft rejection.
Endogenous memory T cell can prevent transplant tolerance and is correlated with poor TX outcome. But under certain circumstances they represent regulatory capacity. For example, after treatment with CTLA-4 Ig and anti-CD159 mAbs in lung TX, Tcm CD8+are essential.
· Treatment for alloreactive T cell memory:
· 1-lymphoablation:
Lymphocyte depletion Anti-bodies in form of induction therapy is commonly used to prevent AMR.
But these drugs are not effective in depletion of memory CD4+ T cell.
Depletion of residual cd4+ T cell impairs the recovery of memory CD8+ T cells after ATG usage.
A synergic effect between ATG and blockage of costimulation.
Alefacept is a fusion protein depletes CD45 RO+ effector / memory T cell and can control effector /memory T cell in TX and have synergist effect with CTLA4-Ig by targeting CD8+ CD2 hi CD28 – T cells is seen.
Recently regulation of cell metabolic pathways is another strategy to target memory T cells.
· 2-Costimulatory blockage:
Memory T cell lose CD28 expression. So, they become resistant to the lack of CD28/B7 costimulation (belatacept). CD57+ CD4+ T cell subsets are belatacept- resistant, too.
Whereas tacrolimus has some effect on this subset.
Limiting trafficking of alloreative memory T cell by blocking chemokines or their receptors is another option.
For example, pre transplant treatment with anti-LFA-1 m Abs can inhibit memory CD8+ T cell.
Conclusion: Alloreactive memory T cell promotes rejection and prevent tolerance.
But use of these information in clinical TX is limited.
Ahmed Omran
3 years ago
Memory T cells develop either due to exposure to peptides from commensal bacteria or environmental antigens ;heterologous immunity or antigen mimicry, exposure to alloantigen eg blood transfusion, pregnancy, prior transplant or through homeostatic proliferation in a set up of lymphopenia.. They reside in and circulate in peripheral non-lymphoid tissue. They are subdivided into different groups :Tcm (central, CCR7+CD62L+), Tem (effector, CD44+CD28+), Temra (effector with CD45RA+), Trm (tissue resident, CD103+CD69+) & Tfh (follicular helper cells, CXCR5+). Memory T cells have significant criteria eg low activation threshold with good effector functions and they resistance to conventional immunosuppression and co stimulation blockade. Memory Helper T cells release interferon gamma leading to DSA formation. Memory CD4+ T cells, with reactivation, leads to effector cells formation and activate donor reactive effector CD8+ T cells resulting in acute rejection. Circulating memory CD8+ T cells, during contact with donor endothelium, result in increased adhesion molecules and chemokines causing infiltration of recipient leukocytes into the graft, their proliferation and interferon release leading to rejection. Memory T cell correlates with poor graft outcomes and is an important obstacle for tolerance. Other obstacles in clinically utilizing data of memory T cells are there regarding diagnostics , the sampling utilizing peripheral blood and non availability of data regarding the tissue resident memory T cells. In addition,, discrepancy in results of animal and human models and susceptibility of the memory T cells to immunosuppression is related to their origin.
MOHAMED Elnafadi
3 years ago
Memory T cells exhibit surface phenotypic markers that distinguish them from naïve counterparts and also reflect their enhanced functional and migration properties. The enhanced expression of activation markers such as CD45RO, and adhesion molecules such as LFA-1 (CD11a) and CD44, on memory vs. naïve T cells are thought to promote efficient interactions with APC and extravasation into inflammatory sites .More recently, expression of the lymph node homing receptors CCR7 and CD62L have been found to vary among memory T cells . In general, expression of CCR7 and CD62L is high in naive cells, connoting their preferred trafficking to lymphoid tissue , whereas memory CD4 and CD8 T cells comprise heterogeneous populations of CCR7+/CD62Lhi and CCR7−/CD62Llo subsets. These phenotypic distinctions have been shown to delineate functional subsets of memory T cells, designated central memory (CD62Lhi/CCR7+) and effector memory (CD62Llo/CCR7−) . The CD62Lhi/CCR7+ memory CD4 T-cell subset from human peripheral blood was found to lack effector function and produce primarily IL-2 , although virus-specific human and mouse central memory CD4 and CD8 T cells were found to exhibit ample effector function . In vivo, central memory CD8 T cells yielded greater protective immunity to LCMV infection in mice compared with the effector-memory subset . Therefore, the effector capacity of memory subsets that differ in homing receptor expression may likely differ according to the antigenic system. It will be important in future studies to establish the respective roles of central and effector memory T cells in allograft rejection.
These variations in homing receptor expression on memory T cells reflect their broad tissue distribution in both lymphoid and nonlymphoid sites including lung, liver, kidney, intestine, and also the brain .It has been shown that memory CD8 T cells in peripheral tissues, unlike memory CD8 T cells in lymphoid tissues, can spontaneously lyse target cells upon antigen reencounter, without the need for clonal expansion and differentiation . Thus, memory T cells have an ‘anatomic advantage’ over naive cells in that they are poised to exhibit immediate function at the site of antigen reencounter, bypassing the need for antigen presentation in the local lymph node. In graft rejection, Lakkis and colleagues have directly demonstrated the relevance of this memory cell advantage by showing that allospecific memory T cells, but not naive T cells, can efficiently reject cardiac allografts in the absence of secondary lymphoid tissue. Thus, memory T cells may have the potential for mediating early rejection responses owing to their rapid trafficking.
Activation requirements and functionOn per cell basis, antigen-specific memory T cells have less stringent activation requirements and exhibit enhanced activation compared with antigen-specific naive T cells. These properties have been demonstrated using T cells isolated from TCR-transgenic mice (TCR-tg) in which a majority of CD4 or CD8 T cells express a defined TCR specific for a given peptide antigen/MHC complex. Using TCR-tg systems, it was found that CD8 memory T cells specific for alloantigen exhibit rapid effector function, faster proliferation, increased responses to low antigen doses and direct cytolytic activity compared with allospecific naive CD8 T cells . Similar analyses have not been accomplished using alloantigen-specific TCR-transgenic CD4 T cells, although TCR-tg CD4 T cells specific for nominal antigenic peptides likewise exhibit immediate effector responses at low antigen doses . Memory T cells therefore have a kinetic and dose–response advantage over naive T cells.
Memory T cells also have less stringent activation requirements and are more permissive to activation by different APCs , compared with naive counterparts. Naive T cells require CD28/B7-mediated costimulation (signal 2) provided by professional APCs such as dendritic cells; however, memory T cells can be fully activated in the absence of costimulation via the B7/CD28 or CD40/CD154 pathways, and by many nonprofessional APC types such as resting B cells and macrophages . Moreover, Pober and colleagues have shown that memory, but not naive, allogeneic CD8 T cells can become activated, expand, and differentiate into cytotoxic T cells by coculture with endothelial cells . When taken together, it is clear that memory T cells, owing to their unique trafficking patterns, reduced activation requirements, and instantaneous recall may not only be the vanguard of T cells to arrive in an allograft, but are also capable of rapidly initiating endothelialitis and vascular rejection.
Effect of Memory T Cells on Allograft SurvivalThe critical role of T cells in ‘second set’ rejection has been established by the demonstration that accelerated rejection of secondary allografts can occur in alloantigen-primed animal models in the complete absence of B cells and circulating antibody . In patients, the presence of alloreactive memory T cells has been more difficult to assess. Sensitized transplant recipients are typically identified based on the presence of circulating anti-HLA antibodies, and it is well known that highly sensitized individuals have increased rejection episodes and inferior graft survival compared with unsensitized recipients . Because T-cell activation is necessary to provide ‘help’ as a prerequisite for B-cell activation and subsequent antibody production, it is likely that these sensitized individuals possess allospecific memory T cells. Heeger and colleagues have directly demonstrated the presence of primed allospecific memory T cells in transplant recipients using a sensitive ELISPOT assay based on cellular quantitation of effector cytokine producers . Using this assay, they provide evidence, in a small cohort of patients, that the pretransplant frequency of primed, donor-reactive cells in recipients of living donor kidneys correlates with the post-transplant risk of developing acute rejection episodes. These studies suggest that the presence of alloreactive memory T cells may impact survival of an allograft.
A major question that emerges when considering memory T cells in the transplant recipient is whether memory T cells are equally susceptible to current immunosuppression regimens. While little is known concerning the effects of immunosuppression on immune memory, the distinct signaling, cytokine, and survival requirements of memory vs. naive T cells suggest that memory T cells and/or memory subsets may be differentially affected by specific immunosuppressants. For example, both mouse and human memory T cells exhibit distinct TCR-mediated signaling compared with naive T cells , potentially affecting their susceptibility to cyclosporine and tacrolimus, which both target the TCR-coupled signaling pathway leading to IL-2 gene transcription. In addition, priming for memory recall responses has been shown to occur in vitro in the presence of cyclosporine , raising the possibility that alloreactive memory T cells could be generated in immunosuppressed individuals.
Other immunosuppressants that target cytokine responses may also differentially affect naive vs. memory T cells. While IL-2 is involved in the clonal expansion of naive T cells, memory CD8 T cells can divide independently of IL-2 and elicit effector function in the absence of division . Therefore, IL-2-receptor blocking drugs that interfere with IL-2 responses of T cells may not inhibit the potent functions and expansion of memory T cells. However, other cytokines, such as IL-7 and IL-15, have been found to affect both memory CD4 and CD8 generation, homeostatic proliferation and/or survival . For memory CD8 T cells, IL-15 is required for their homeostatic proliferation in vivo, but appears dispensable for antigen-driven proliferation . While memory CD4 T cells do not require IL-15 for homeostasis, IL-7 appears important for memory CD4 T-cell generation and survival . These results suggest that interfering with responses to IL-7 and IL-15 may affect the generation, survival and/or homeostatic turnover of memory T cells in vivo.
Resistance of Memory T Cells to Tolerance InductionInduction of donor-specific immunologic tolerance remains the ultimate goal in transplantation. Over the past several decades, a great deal has been learned about the mechanisms regulating primary immune responses, including utilization of adhesion molecules, chemokines, costimulatory pathways, and signaling pathways. Based on this knowledge, numerous strategies have been developed in small animal models, which have resulted in significantly prolonged allograft survival or even tolerance induction . Costimulation blockade of the CD154/CD40 pathway in the presence of donor-specific transfusion (DST) has been remarkably successful in promoting permanent survival of heart and islet allografts. However, this same strategy is wholly ineffective if the recipient has been previously primed with donor-specific antigen . Likewise, infection with Leischmania major or LCMV has been shown to generate primed T cells specific for certain mouse haplotypes, and this cross-reactive, allospecific memory is also refractory to tolerance induction strategies using costimulation blockade. Similarly, a regimen of combined CD28/CD40L blockade in combination with donor bone marrow and nonmyelosuppressive conditioning results in donor-specific tolerance of C57/BL6 hosts to BALB/c skin grafts, which does not occur if the recipient has been previously infected with LCMV. These results indicate that alloreactive memory T cells can mount effective rejection responses in the absence of costimulation, consistent with in vitro results . It has been suggested that failure of costimulation-based tolerance induction strategies in large animals may be owing to the increased proportion of memory T cells in these hosts compared with young rodents housed in pathogen-free conditions ; however, this idea has not yet been subject to experimental testing.
Additional evidence suggesting the refractory nature of memory T cells to tolerance induction strategies derives from studies on autoimmune type I diabetes. Transplantation of syngeneic islets into autoimmune diabetic NOD mice results in rapid destruction of islet grafts, characteristic of a secondary response, and referred to as recurrent autoimmunity. Numerous strategies shown to prevent primary disease in NOD mice are ineffective against recurrent autoimmunity in islet T-cell transplantation, where reactivation of memory T cells is likely to occur.
Despite their insensitivity to costimulation blockade in vivo, memory T cells are not inherently refractory to tolerance induction. For example, in vivo tolerization of antigen-specific mouse memory CD4 and CD8 T cells has been shown to occur following administration of high doses of intravenous soluble peptide antigen or low-avidity agonist-altered peptide ligands . Crosspresentation of peptide antigens by resting APC can also induce tolerance of memory T cells ( In addition, we have shown that memory T cells are not terminally differentiated, but rather can display functional flexibility and plasticity and recently, it has been shown that memory CD8 T-cell responses to allografts can be inhibited by CD4+ CD25+ regulatory T cells in vivo . When taken together, these results suggest that memory T cells are amenable to functional modulation. Further studies elucidating the mechanisms of memory T-cell functional plasticity and modulation will be critical in the rational design of strategies to induce tolerance of allospecific memory T cells.
Potential roles for memory T cells in transplant rejectionThe enhanced functional properties and diversity of memory T cells discussed above suggest that memory T cells may potentially participate in early and late graft rejection by a number of different mechanisms,. Because effector-memory T cells can recirculate in peripheral tissues, memory T cells may be rapidly recruited and initiate early responses directly at the graft site. These effector-memory T cells could immediately produce effector cytokines in situ that recruit additional immune cells for early graft tissue damage .
Abdullah Raoof
3 years ago
memeory T cell are characterized by
· low activation threshold
· robust effector function
· resistant to conventional immunosuppression and costimulation blockade .
T cells reside in and circulate through non lymphoid tissue .
Alloreactive memory T cells are subdivided into different categories based on their origin, phenotypes and function.
Sensitized individual display high alloreactive memort Tcells.
Allorective memeory T cells has major role in graft rejection and prevention of graft tolerance.
Immune response against antigens are beneficial during infection ,vaccinations, and tumor surveillance . Conversely, allorective T cell immune response against alloantigens in graft is detrimental.
Despite the potential harmfull effect of memory T cell ,its impact is neglected while choosing treatment regimens.
Memory Tcells comprises about 5-10% of all T cells .
heterologous immunity :- it is situation in which the memory cells is produced by recognition of peptide from bacteria or environmental antigens presented by self-MHC, which can mimic complexes formed by allogeneic MHC molecules bound to other peptides.
In humans, sensitization occur by previous transplants, pregnancies, and blood transfusions.
Prolonged dialysis increases the risk of developing alloreactive memory T Cells .
low serum levels of 25-OH-vitamin D in dialysis patients correlates with
the frequency of alloreactive memory T cells.
Memory T cells have been traditionally divided into two major subsets with largely overlapping functions but distinct trafficking patterns
· Central memory T cells (Tcm)
· effector memory T cells
In the process of memory T cell differentiation, the T cell
receptor and costimulatory signaling cascades are adjusted to ensure rapid activation of high magnitude upon antigen reencounter. This results in the ability of memory T cells to respond to lower antigen doses with limited costimulation, i.e., to antigen presented by non-professional antigen-presenting cells .While this process is essential for host defense, it renders alloreactive memory T cells more dangerous in transplant settings.
While de novo responses by naïve T cells can be efficient controlled by current immunosuppression, memory CD4+ T cells are resistant to these therapies and can provide help for the generation of DSA leading to alloantibody-mediated graft injury.
The potential therapeutic targets to control CD40-independent DSA generation by memory CD4+ T cells.
First, gamma interferon (IFNγ) secretion by memory helper T
cells is required for de novo DSA generation .
Second, CD40- independent helper functions of donor-reactive memory CD4+ T cells and heart allograft rejection were markedly inhibited by
neutralizing B cell activating factor and a proliferation-inducing ligand, cytokines critical for B cell survival, activation, and differentiation.
The presence of memory T cells has been often correlated with poor outcomes in clinical transplantation.
presence of memory T cells pretransplantation has been associated with an increased risk for acute rejection of kidney transplants . However, while EBV- and CMV-specific memory T cells displaying alloreactivity have been detected in human transplant recipients, so far there is no indication that the presence of “heterologous immunity” in transplant recipients correlates with worse graft outcomes.
Induction therapy is widely used in clinical transplantation to overcome the deleterious effects of preexisting donor-reactive immunity. Antibody-mediated lymphocyte depletion is most commonly used induction strategy, particularly in highly sensitized patients and in patients receiving marginal grafts. Although memory T cells are the primary targets of induction therapies, they are less susceptible to depletion than naïve T cells . The efficiency of memory CD4+ T cell depletion is generally lower than that of CD8+ T cells.
Belatacept, a second generation of CTLA4-Ig, is currently used to minimize the toxic side effects of calcineurin inhibitors. Despite reduced side effects and improved graft survival, belatacept-treated patients have higher rates of acute cellular rejection compared to CNI treatment . As memory T cells are more resistant to the effects of CTLA4-Ig in animal transplantation models, it is possible that presensitized T cells could account for some belatacept-resistant rejection episodes.
Not surprisingly, increased numbers of both CD4+ and CD8+ CD28- memory T cells are associated with a poor outcome in renal and lung transplant patients.
One study demonstrated that the sensitivity of memory T cells to immunosuppression is dependent on their origin.
CONCLUDING REMARKS.
other types of immunologic memory lymphocytes such as memory B cells, preexisting alloantibodies, and “innate memory” described for NK cells and macrophages can impact transplant outcomes, in this review, we focused exclusively on T cell memory.
It is now firmly established that alloreactive memory T cells accelerate allograft rejection and prevent transplant tolerance.
Difficulties First, the diagnostics of T cell allosensitization in transplant candidates is problematic. Due to heterogeneity in phenotype and functions of memory T cells, complementary tests will be required including analyses of cytokine producing, cytotoxic, and follicular helper T cells. Second, memory T cells in humans are sampled only in peripheral blood. So far, there is no information on pathogenicity of tissue-resident alloreactive memory T cells. Third, memory T cell susceptibility to immunosuppression may depend on their origins. As immunological histories of individuals are difficult to trace, the situation may arise when patients with similar T cell memory profile require distinct treatment strategies. Finally, despite rapidly accumulating data on alloreactive T cell memory, the discrepancies between animal models and transplantation in human patients
are profound.
Mohammed Sobair
3 years ago
BASIC BIOLOGY OF ALLOREACTIVE MEMORY T CELLS Origins of
Alloreactive Memory T Cells:
Alloreactive memory T cells recognize intact allogeneic MHC molecules through
Direct allorecognition pathway.
Indirectly as donor peptides–self-MHC complexes
It is probable that sensitized patients exhibiting high titers of all specific antibodies
display memory T cells recognizing alloantigens.
Memory T cells can also be generated through homeostatic proliferation in a
lymphopenic environment, including potentially alloreactive and pathogenic T cells.
The risk of developing alloreactive t cell increase also with:
Prolonged exposure to dialysis increases memory T cell.
In addition low serum levels of 25-OH-vitamin D in dialysis patients correlates with
the frequency of alloreactive memory T cell.
Location of Memory T Cells:
Memory T cells divided into two major subsets:
Central memory T cells (Tcm) express lymphoid homing markers CCR7 and
CD62L.
Effector memory T cells (Tem) are CCR7−CD62L.
Some T cells in peripheral tissues represent a distinct subset of tissue-resident
memory T cells, Trm cells express early activation marker CD69 and αEβ7 integrin
CD103 along with a number of tissue-specific chemokine receptors.
There is accumulating evidence that Trm cells play an important role in host
protection against infections AND transplant rejection.
Low Activation Threshold and Resistance to Conventional Costimulatory
Blockade:
In the process of memory T cell differentiation, the T cell receptor and
costimulatory signaling cascades are adjusted to ensure rapid activation of high
magnitude upon antigen reencounter This results in the ability of memory T cells to
respond to lower antigen doses with limited costimulation, i.e., to antigen presented
by non-professional antigen-presenting cells . While this process is essential for
host defense, it renders alloreactive memory T cells more dangerous in transplant
settings. Numerous studies in animal models have demonstrated that donor-
reactive memory T cells can induce allograft rejection despite interruption of
essential costimulatory pathways, CD28/CD80/CD86 and CD40/CD154
CONTRIBUTION OF MEMORY T CELLS TO ALLOGRAFT REJECTION AND
TOLERANCE:
Role in Allograft Rejection:
Memory CD4+ T cells not only become effector cells upon reactivation, but also
provide help for the activation of donor-reactive effector CD8+ T cells. These
effector CD8+ T cells then are the main driving force behind allograft rejection.
Memory CD4+ T cells are resistant to these therapies and can provide help for the
generation of DSA leading to AMR.
direct contact of circulating memory CD8+ T cells with donor endothelium
upregulates the expression of adhesion molecules and chemokines thus facilitating
infiltration of recipient leukocytes into the graft .
A proportion of endogenous memory CD8+ T cells react to donor MHC class I
molecules and can infiltrate allografts within hours after reperfusion. Once in the
graft parenchyma, these memory CD8+ T cells proliferate extensively, upregulate
the expression of ICOS, and secrete IFNγ in ICOS-dependent manner.
Influence of Memory T Cells on Allograft Tolerance:
T cells are generally viewed as pathogenic in the context of transplantation, under
certain circumstances, they demonstrate regulatory capacity and suppress
deleterious pro-inflammatory immune responses.
RECENT DEVELOPMENTS IN TARGETING ALLOREACTIVE T CELL MEMORY:
Lymphoablation:
Memory T cells are the primary targets of induction therapies, they are less
susceptible to depletion than naïve T cells.
T cells with an effector/memory phenotype are detectable after anti-CD52 mAb or
ATG induction and are associated with acute rejection episodes human transplant
recipients.
Limiting CD4+ T helper signals during lymphoablation increases the efficacy of
mATG in controlling memory T cell expansion and significantly extends heart
allograft survival in sensitized recipients These findings are consistent with
previous observations describing a synergistic effect between ATG lymphoablation
and costimulatory blockade.
Alefacept selectively depletes this subset and spares other T cell population.
Costimulatory Blockade:
Belatacept, a second generation of CTLA4-Ig, is currently used in clinical
transplantation to prevent allograft rejection. As memory T cells are more resistant
to the effects of CTLA4-Ig in animal transplantation models, it is possible that
presensitized T cells could account for some belatacept-resistant rejection
episode.
Limiting Trafficking of Alloreactive Memory T Cells:
Pretransplant treatment with anti-LFA-1 mAbs inhibited early infiltration of
endogenous donor-reactive memory CD8+ T cells into cardiac allografts, and
significantly prolonged allograft survival (135). These findings suggest that a short
course of integrin blockade may be instrumental in controlling T cell memory while
avoiding side effects of long-term treatments.
CONCLUDING REMARKS:
Alloreactive memory T cells accelerate allograft rejection and prevent transplant
tolerance.
Implementation of accumulated experimental knowledge in clinical transplantation
is impeded by several factors:
First, the diagnostics of T cell Allosensitization in transplant candidates is
problematic.
Second, memory T cells in humans are sampled only in peripheral blood. So far,
there is no information on pathogenicity of tissue-resident alloreactive memory T
cells.
Third, memory T cell susceptibility to immunosuppression may depend on their
origins.
Mohamed Essmat
3 years ago
Memory CD 4 T cell has a role in reactivation and also help donor-reactive effector CD8+ T cells which play a major role in allograft rejection so decreasing or depleting effector CD8+ T increase graft survival. CD 4 T cell helps for the generation of DSA leading to alloantibody-mediated graft injury and unfortunately resistant to current immunosuppression. Direct contact of circulating memory CD8+ T cells with donor endothelium upregulates the expression of adhesion molecules and chemokines thus facilitating infiltration of recipient leukocytes into the graft which increases risk of rejection and prolonged cold ischemia aggravate this cascade. Allograft tolerance:The presence of memory T cells pre-transplantation are associated with an increased risk for acute rejection of kidney transplant but “heterologous immunity” in transplant recipients doesn’t correlates with worse graft outcomes ,so lymph ablative approaches targeting memory T cells may interfere with allograft acceptance of certain types of transplants. Targeting allo-reactive memory cells:
Lymphoablation: One of the most important strategy in sensitized recipients is induction therapy by ATG or alemtuzumab which is directed mainly to Memory T cells but its efficacy is less than naïve T cell.
Alefacept, a fusion protein which binds to CD2which is expressed on effector/memory T cells and depleting them so its used for targeting
costimulatory blockade-resistant CD8+CD2hiCD28 effector/memory T cells as coeffect for CTLA4-Ig . Costimulatory Blockade: Belatacept, a second generation of CTLA4-Ig, is currently used in clinical transplantation to prevent allograft rejection but terminally differentiated memory CD4+ and CD8+ T cells in humans (Temra) lose CD28 expression so become insensitive to CTLA4-Ig due to the lack of CD28/B7 co-stimulation.
saja Mohammed
3 years ago
Role of Memory T Cells in Allograft Rejection and Tolerance BASIC BIOLOGY OF ALLOREACTIVE MEMORY T CELLS
T central memory cells (Tcm), express CCR7 chemokines which circulate through non lymphoid peripheral tissue and central lymphoid tissues with more proliferative activities
T effector memory cells (Tem ) express the chemokine receptor CXCR3 but lack CCR7, circulate more In nonlymphoid peripheral tissue and spleen , with immediate effect or function .
Tm cells have many advantages compared to their naïve T cells
More expression with longer half span wider migration pattern in lymphoid and nonlymphoid tissues need lower thresholds for reactivation with a strong recall immune response that resistant to treatment with CTLA4 Ig ( Belatocepts) as its recall immune response not dependent on costimulatory pathway , Tm cells reactivity mainly due to acquired alloreactive response to infection ,vaccination frequently due to cross reactivity with alloantigen . Second, alloreactive TM arise after exposure to alloantigen’s in blood transfusions, previous organ transplants, or pregnancy. Third, alloreactive TM arise during recovery from lymphopenia after induction with T cell depleting agents like ATG, alemtuzumab.
Tm cells can be activated can be activated outside secondary lymphoid organs—for example, in the graft itself.
prescence of pretransplant allogenic Tm cells assocaited with increase risk of acute rejection in presentized patinets
they are more resistant to depleting agents compared to naive cells
their effect on inducing tolererance depending on thier inhibitory expression ,data limited to animal studies,including trails trying to reduce the expression of different chemkinases at allogenic Tm activator receptors which may prevent graft rejction and imporve graft survival .
nawaf yehia
3 years ago
Several types of immunologic memory lymphocytes such as memory B cells, memory T cells ,preexisting alloantibodies, and “innate memory” described for NK cells and macrophages can impact transplant outcomes .Alloreactive memory T cells represent an essential element of the allograft rejection process and a major barrier to tolerance induction in clinical transplantation . they are characterized by their low activation threshold, robust effector functions, and resistance to conventional immunosuppression and costimulation blockade. therefore memory immune responses against donor antigens are detrimental in the context of transplantation and are commonly associated with poor graft outcome.
Origins of Alloreactive Memory T Cells : It is likely that these memory cells are generated through the 1)recognition of peptides from commensal bacteria or environmental antigens presented by self-MHC, which can mimic complexes formed by allogeneic MHC molecules bound to other peptides .
2) transplant patients can be sensitized from exposures to alloantigens such as previous transplants, pregnancies, and blood transfusions .
3) Memory T cells can also be generated through homeostatic proliferation in a lymphopenic environment, including potentially alloreactive and pathogenic T cells .
4) The accumulation of alloreactive memory T cells may be influenced by the end stage organ disease or treatment common in transplant candidates. For example, prolonged exposure to dialysis increases the risk of developing alloreactive memory T cells. In addition, Sawinski et al. reported that low serum levels of 25-OH-vitamin D in dialysis patients correlates with the frequency of alloreactive memory T cells independent of age, gender, previous transplants, or time on dialysis . Location of Memory T Cells : Memory T cells have been traditionally divided into two major subsets with largely overlapping functions but distinct trafficking patterns. Central memory T cells (Tcm) express lymphoid homing markers CCR7 and CD62L, whereas effector memory T cells (Tem) are CCR7−CD62L− but instead express molecules that promote migration into peripheral tissues .
Recent studies demonstrated that some T cells in peripheral tissues do not circulate and represent a distinct subset of tissue-resident memory T cells (Trm) .There is accumulating evidence that Trm cells play an important role in host protection against infections. It is conceivable that Trm cells of both donor and recipient origins may influence transplant outcome by facilitating GVHD or allograft rejection, respectively . RECENT DEVELOPMENTS IN TARGETING ALLOREACTIVE T CELL MEMORY
Lymphoablation Induction therapy is widely used in clinical transplantation to overcome the deleterious effects of preexisting donor-reactive immunity. Antibody-mediated lymphocyte depletion is most commonly used induction strategy, particularly in highly sensitized patients and in patients receiving marginal grafts Although memory T cells are the primary targets of induction therapies, they are less susceptible to depletion than naïve T cells ). T cells with an effector/memory phenotype are detectable after anti-CD52 mAb or ATG induction and are associated with acute rejection episodes. The efficiency of memory CD4+ T cell depletion is generally lower than that of CD8+ T cells Additional depletion of residual CD4+ T cells severely impairs the recovery of memory CD8+ T cells after ATG treatment .Limiting CD4+ T helper signals during lymphoablation increases the efficacy of mATG in controlling memory T cell expansion. These findings are consistent with previous observations describing a synergistic effect between ATG lymphoablation and costimulatory blockade). Alefacept, a fusion protein combining extracellular domain of LFA-3 with constant regions of human IgG1 LFA-3 is a ligand for CD2, a molecule that is predominantly detected on human T and NK cells. As CD2 expression is upregulated on CD45RO+ effector/memory T cells, alefacept selectively depletes this subset and spares other T cell populations Alefacept is currently being used in clinic for the treatment of severe psoriasis and is showing promise for targeting alloreactive effector/memory T cells in solid organ and bone marrow transplantation. Most importantly, pretransplant alefacept therapy synergizes with CTLA4-Ig presumably by targeting costimulatory blockade-resistant CD8+CD2hiCD28− effector/ memory T cells (91). In addition to direct lymphoablation, manipulating T cell survival and homeostasis by regulating cell metabolic pathways may be a promising therapeutic strategy in transplantation. Costimulatory Blockade Belatacept, a second generation of CTLA4-Ig, is currently used in clinical transplantation to prevent allograft rejection and minimize the toxic side effects of calcineurin inhibitors. Despite reduced side effects and improved graft survival, belatacept-treated patients have higher rates of acute cellular rejection compared to CNI treatment . As memory T cells are more resistant to the effects of CTLA4-Ig in animal transplantation models, it is possible that presensitized T cells could account for some belatacept-resistant rejection episodes. Indeed, terminally differentiated memory CD4+ and CD8+ T cells in humans (Temra) lose CD28 expression and become insensitive to the lack of CD28/B7 costimulation). Not surprisingly, increased numbers of both CD4+ and CD8+ CD28− memory T cells are associated with a poor outcome in renal and lung transplant patients.
another major costimulatory pathway, CD40/CD154, encountered early difficulties because of thromboembolic effects of anti-CD154 (CD40L) blocking antibodies .To avoid cross-linking CD154 that is highly expressed on platelets, an alternative approach has been the generation of non-activating anti-CD40 antibodies. Several such reagents have been successfully tested in non-human primate recipients of renal and islet allografts Limiting Trafficking of Alloreactive Memory T Cells : While preventing memory T cell entrance into graft tissue should improve transplant outcome, the attempts to neutralize chemokines or chemokine receptors such as CCR5 or CXCR3 did not live up to the initial expectations, most likely due to the redundancy of chemokine/receptor network
Theepa Mariamutu
3 years ago
Memory T cells constitute around 5-10% of all T cells in mice. In the absence of prior exposure to antigens, only 1-10% can react to allogeneic MHC, the source of these memory cells is infection and exposure to environmental antigens ( heterologous immunity).
Memory T cells can also be generated through homeostatic proliferation in a lymphopenic environment and can impair tolerance to allografts.
The accumulation of these memory cells can be affected by the end-organ disease such as in patients with ESRD, prolonged exposure to dialysis & the low level of 25 OH-vitamin D in these patients lead to the development of memory cells.
Location of memory T cells:
central memory T cells: express CCR7 and CD62L. -harder to control
Effector memory T cells: express CCR7, CD62L.
CD4+CXCR5hi Tfh cells: resides in B cell follicles and are essential for B cells responses and antibody generation.
Memory T cells are characterized by a low activation threshold and resistance to costimulatory blockade and this results in the ability of memory T cells to respond to lower antigen doses with limited co-stimulation.
Role in allograft rejection:
Upon activation of memory CD4+ T cells, they become effector cells & also provide help for the activation process of CD8+ T cells. These effector CD8+ T cells are the main driving force for rejection. Early direct contact of these cells with donor endothelium upregulates the expression of adhesion molecules and chemokines thus facilitating infiltration of the recipient leukocytes into the graft.
Memory CD4+ T cells are resistant to immunosuppressive medications and can provide help for DSA formation & ABMR.
Influence of memory T cells on allograft tolerance:
The presence of memory T cells Pre- transplantation has been associated with an increased risk of acute rejection, however, there is no indication that the presence of heterologous immunity( such as EBV, CMV-specific memory T cells) correlates with worse graft outcomes.
Under certain circumstances, memory T cells show a regulatory effect and suppress the pro-inflammatory immune response and there is concern about the lymphoablative approaches targeting memory T cells may interfere with allograft acceptance of certain types of transplants.
Recent developments in targeting alloreactive T cell memory
Lymphoablation: ATG, Alemtuzumab- less effective. Alefacept a recombinant dimeric fusion protein inhibits LFA3/ CD2 interaction and thus inhibits T cells activation, selectively depletes memory T cells, currently used for the treatment of psoriasis.
costimulatory blockade: Belatacept second generation of CTLA4-Ig is currently used to prevent rejection and minimize the toxic effect of CNI, but there is an increased incidence of cellular rejection compared to CNI as memory cells are more resistant to the effect of CTLA4-Ig and terminally differentiated memory CD4+, CD8+ T cells lose CD28 expression.
Limiting trafficking of alloreactive memory T cells: reagents blocking LFA-1 & VLA-4 have been demonstrated to prolong allograft survival in experiments.
Dalia Ali
3 years ago
alloreactive memory T cells represent an essential element of the allograft rejection process and a major barrier to tolerance induction in clinical transplantation
Origins of Alloreactive Memory T Cells
these memory cells are generated through the recognition of peptides from commensal bacteria or environmental antigens presented by self-MHC, which can mimic complexes formed by allogeneic MHC molecules bound to other peptides
For instance, following an EBV infection, HLA-B8+ individuals can become sensitized to the allo-MHC molecule HLA-B4402 through antigen mimicry resulting from the presentation of some viral or parasitic peptides
In humans, transplant patients can be sensitized from exposures to alloantigens such as previous transplants, pregnancies, and blood transfusions.
The accumulation of alloreactive memory T cells may be influenced by dialysis, low serum levels of 25-OH-vitamin D in dialysis patients correlates with the frequency of alloreactive memory T cells independent of age, gender, previous transplants, or time on dialysis
Location of Memory T Cells
Central memory T cells (Tcm) express lymphoid homing markers CCR7 and CD62L and
effector memory T cells (Tem) are CCR7−CD62L− express molecules that promote migration into peripheral tissues
memory T cells in secondary lymphoid and non-lymphoid peripheral tissues are spared by antibody-mediated lymphoablation
Low Activation Threshold and Resistance to Conventional Costimulatory Blockade
the T cell receptor and costimulatory signaling cascades are adjusted to ensure rapid activation of high magnitude upon antigen reencounter
This results in the ability of memory T cells to respond to lower antigen doses with limited costimulation, i.e., to antigen presented by non-professional antigen-presenting cells .
Role in Allograft Rejection
memory CD4+ T cells not only become effector cells upon reactivation, but also provide help for the robust activation of donor-reactive effector CD8+ T cells
These effector CD8+ T cells then are the main driving force behind allograft rejection facilitated by memory CD4+ T cells in heart-transplanted mice, and CD8+ T cell depletion or limiting their trafficking into the graft significantly extends allograft survival
While de novo responses by naïve T cells can be efficiently controlled by current immunosuppression, memory CD4+ T cells are resistant to these therapies and can provide help for the generation of DSA leading to alloantibody-mediated graft injury
influence of Memory T Cells on Allograft Tolerance
In laboratory rodents, endogenous memory T cells generated through heterologous immunity have little ability to prevent tolerance induction given that hematopoietic chimerism and/ or costimulation blockade regularly achieve tolerance of fully allogeneic transplants
In contrast, mice that have been sensitized to allogeneic MHC through transplantation or multiple viral infections become resistant to tolerance induction
Lymphoablation
memory T cells are the primary targets of induction therapies, they are less susceptible to depletion than naïve T cells
T cells with an effector/memory phenotype are detectable after anti-CD52 mAb or ATG induction and are associated with acute rejection episodes in non-human primates and human transplant recipients
The efficiency of memory CD4+ T cell depletion is generally lower than that of CD8+ T cells
Additional depletion of residual CD4+ T cells severely impairs the recovery of memory CD8+ T cells after ATG treatment
Costimulatory Blockade
Belatacept, a second generation of CTLA4-Ig, is currently used in clinical transplantation to prevent allograft rejection and minimize the toxic side effects of calcineurin inhibitors (97). Despite reduced side effects and improved graft survival, belatacept-treated patients have higher rates of acute cellular rejection compared to CNI treatment
As memory T cells are more resistant to the effects of CTLA4-Ig in animal transplantation models
Limiting Trafficking of Alloreactive Memory T Cells
pretransplant treatment with anti-LFA-1 mAbs inhibited early infiltration of endogenous donor-reactive memory CD8+ T cells into cardiac allografts, and significantly prolonged allograft survival
Conclusion
alloreactive memory T cells accelerate allograft rejection and prevent transplant tolerance.
diagnostics of T cell allosensitization in transplant candidates is problematic
memory T cells in humans are sampled only in peripheral blood. So far, there is no information on pathogenicity of tissue-resident alloreactive memory T cells
memory T cell susceptibility to immunosuppression may depend on their origins
amiri elaf
3 years ago
# This article describes the different subsets of alloreactive memory T cells involved in transplant rejection, their generation, functional properties, mechanisms of action and discuss strategies developed to target deleterious allospecific memory T cells in experimental animal models and clinical settings.
* Memory T cells are characterized by:
low activation threshold
robust effector functions
resistance to conventional immunosuppression and costimulation blockade.
– Reside in and recirculate through peripheral non-lymphoid tissues. Alloreactive memory T cells are subdivided into different categories based on their origins, phenotypes, and functions.
– These memory cells are generated through the recognition of peptides from commensal bacteria or environmental antigens presented by self-MHC, which can mimic complexes formed by allogeneic MHC molecules bound to other peptides .
– This antige mimicry named “heterologous immunity,” is well documented in both humans and experimental animal models.
– After EBV infection, HLA-B8+ individuals can become sensitized to the allo-MHC molecule HLA-B4402 through antigen mimicry resulting from the presentation of some viral or parasitic peptides
– Alloreactive memory T cells essential element of the allograft rejection
– A major barrier to tolerance induction in clinical transplantation.
– Memory immune responses against
donor antigens are commonly associated with poor graft outcome.
– Despite well documented harmful effects of memory T cells in
transplantation the potential impact of such cells is mostly neglected while choosing treatment regimens.
– Transplant patients can be sensitized from exposures to alloantigens such as previous transplants, pregnancies, and blood transfusions.
– Sensitized patients exhibiting high titers of allospecific antibodies display memory T cells recognizing alloantigens indirectly as donor peptides–self-MHC complexes.
– Memory T cells can also be generated through homeostatic proliferation in a lymphopenic environment, including potentially alloreactive and pathogenic T cells .
– Such homeostatically expanded memory T cells can impair tolerance induction to allografts .
-Prolonged exposure to dialysis increases the risk of developing alloreactivememory T cells .
– Low serum levels of 25-OH-vitamin D in dialysis patients correlates with the frequency of alloreactive memory T cells independent of age, gender, previous transplants, or time on dialysis.
# Location of Memory T Cells
– Memory T cells have been traditionally divided into two
* Central memory T cells (Tcm)
express lymphoid homing markers CCR7 and CD62L.
* Effector memory T cells (Tem)
are CCR7−CD62L− but instead
express molecules that promote migration into peripheral tissues .
* Terminally differentiated effector memory T cells (Temra)
reexpress naive T cell surface marker CD45RA, while downr egulating expression of CCR7, CD62L, and CD28, and represent a terminal stage of effector differentiation .
– Resident memory T cells (Trm)
in peripheral tissues do not circulate and represent a distinct subset of tissue
express early activation marker CD69 and αEβ7 integrin CD103 along with
a number of tissue-specific chemokine receptors play an important role in host protection against infections. It may influence transplant outcome by facilitating GVHD or allograft rejection
* follicular helper cell (Tfh)
express CD4+CXCR5hi that reside in B cell follicles within secondary lymphoid organs and are essential for optimal B cell responses and antibody generation
Memory T cells in secondary lymphoid and non-lymphoid peripheral tissues are spared by antibody-mediated lymphoablation ,Trm cells may be harder to control compared to circulating memory T cells.
# Low Activation Threshold and Resistance to Conventional Costimulatory Blockade:
– Ability of memory T cells to respond to lower antigen doses with limited co- stimulation to antigen presented by non professional antigen presenting cells.
– While this process is essential for host defense, it renders alloreactive memory T cells more dangerous in transplant .
# CONTRIBUTION OF MEMORY T CELLS
TO ALLOGRAFT REJECTION AND
TOLERANCE
* Role in Allograft Rejection
– Memory CD4+T cells not only become effector cells upon reactivation, but
also provide help for the robust activation of donor-reactive effector CD8+ T cells -These effector CD8+ T cells then are
the main driving force behind allograft rejection facilitated bymemory CD4+ T cells .
– De novo responses by naïve T cells can be efficiently controlled by current immunosuppression.
– Memory CD4+T cells are resistant to these therapies and can provide help
for the generation of DSA leading to alloantibody-mediated graft injury.
– Gamma interferon (IFNγ) secretion by memory helper T cells is required for de novo DSA generation .
– Early direct contact of circulating memory CD8+ T cells with donor
endothelium upregulates the expression of adhesion molecules, chemokines and infiltration of recipient leukocytes into the graft .
# Influence of Memory T Cells on Allograft Tolerance:
– presence of memory Tcells pretransplantation has been
associated with an increased risk for acute rejection of kidney transplants . -EBV and CMV specific memory T cells displaying alloreactivity have been detected in human transplant recipients, there is no indication that the presence of “heterologous immunity” in transplant recipients correlates with
worse graft outcomes .
# RECENT DEVELOPMENTS IN TARGET
ALLOREACTIVE T CELL MEMORY
* Lymphoablation
– Antibody-mediated lymphocyte depletion is most commonly used induction strategy, particularly in highly sensitized patients and in patients receiving marginal grafts .
– Memory T cells are the primary targets of induction therapies, but they are less susceptible to depletion than naïve T cells , T cells with an effector/memory phenotype are detectable after anti-CD52 mAb or ATG induction and are associated with acute rejection episodes .
– The efficiency of memory CD4+ T cell depletion is generally lower than that of
CD8+ T cells .
– Alefacept, a fusion protein combining extracellular domain of LFA-3 with human IgG1 it depletes this subset and spares other showing promise for targeting alloreactive effector/memory T cells in solid organ and bone marrow transplantation .
– pretransplant alefacept therapy synergizes with CTLA4-Ig presumably by targeting costimulatory blockade-resistant CD8+CD2hiCD28− effector/memory T cells .
* Costimulatory Blockade
-Belatacept a second generation of CTLA4-Ig used in clinical transplantation to prevent allograft rejection and minimize the toxic side effects of CNI, it
treated patients have higher rates of acute cellular rejection compared to CNI treatment .
presensitized T cells could account for some belatacept-resistant rejection episodes.
– Terminally differentiated memory CD4+ and CD8+ T cells in humans lose CD28 expression and become insensitive to the lack of CD28/B7 costimulation.
– Increased numbers of both CD4+ and CD8+CD28− memory T cells are associated with a poor outcome in
renal and lung transplant
# CONCLUDING REMARKS
– Alloreactive memory T cells accelerate allograft rejection and prevent transplant tolerance.
– The diagnostics of T cell allosensitization in transplant candidates is problematic.
– Due to heterogeneity in phenotype and functions of memory T cells, complementary tests will be required.
The resulting information is hard to
use in clinical decision-making.
– No information on pathogenicity of tissue-resident alloreactive memory T cells.
– Finally, despite rapidly accumulating data on alloreactive T cell memory, the discrepancies between animal models and transplantation in human patients
are profound.
Amit Sharma
3 years ago
Role of Memory T Cells in Allograft Rejection and Tolerance Memory T cells are a type of T lymphocytes generated either through exposure to peptides from commensal bacteria or environmental antigens (heterologous immunity or antigen mimicry), exposure through alloantigen (like blood transfusion, pregnancy, prior transplant etc) or through homeostatic proliferation in a lymphopenic environment. They stay in and circulate through peripheral non-lymphoid tissue. They can be subdivided into different groups including Tcm (central, CCR7+CD62L+), Tem (effector, CD44+CD28+), Temra (effector with CD45RA+), Trm (tissue resident, CD103+CD69+) and Tfh (follicular helper cells, CXCR5+). The memory T cells have low activation threshold with good effector functions and they are resistant to conventional immunosuppression and costimulation blockade. Memory Helper T cells release interferon gamma leading to DSA generation. Memory CD4+ T cells, on reactivation, give rise to effector cells and also activate donor reactive effector CD8+ T cells leading to acute rejection. Circulating memory CD8+ T cells, on contact with donor endothelium, lead to increased adhesion molecules and chemokines causing infiltration of recipient leukocytes into the graft, their proliferation and interferon release causing rejection. Memory T cell presence correlates with poor graft results and is a major obstacle to achieve tolerance. There are still many obstacles in utilizing the data on memory T cells clinically as the diagnostics are not easy, the sampling utilized is peripheral blood and no data exists regarding the tissue resident memory T cells. In addition, the results of animal and human models are not comparable and susceptibility of the memory T cells to immunosuppression depends on their origin.
Weam Elnazer
3 years ago
Memory T cells increase the likelihood of graft rejection and decrease the likelihood of transplant tolerance.
The biology of alloreactive memory T cells at their most fundamental level
The following is the source:
The generation of memory cells following the detection of peptides from commensal bacteria or environmental antigens presented by the self-MHC is referred to as heterologous immunity. Patients undergoing transplantation who have been exposed to alloantigens, such as during pregnancy, blood transfusion, or a prior transplant, may develop sensitization.
T cells with the potential to be alloreactive and pathogenic may be created by homeostatic proliferation in a lymphopenic environment, among other things.
These cells may be created in individuals with end-stage organ illness; for example, dialysis increases the likelihood of the development of alloreactive memory T cells, and research found that low vitamin D levels in dialysis patients are associated with the frequency of alloreactive memory T cells.
Location:
Memory is the brain’s hippocampus T cells (Tcm) express lymphoid homing markers, which help them to find their way home.
Effector memory is a term used to describe the memory of an effector. T cells (Tem) produce chemicals that aid in the cell’s migration to peripheral organs.
Tissue-resident memory is a kind of memory that is found in tissues. Despite the fact that T cells are protective against infection, T cells in the recipient increase the likelihood of allograft rejection (its role in transplant is not well addressed)
Follicular helper cells (Tfh) are cells that reside in the B cell follicle of the secondary lymphoid organ and are essential for the development of the B cell response and the production of antibodies.
The low activation threshold and resistance to traditional costimulatory inhibition are two characteristics of this receptor.
They are more harmful in transplant because they react to modest antigen dosages with minimal costimulation, making them more deadly in transplant.
The role of the immune system in allograft rejection:
memory When CD4 T cells are reactivated, they become effector cells that aid in the activation of CD8 T cells as well as the creation of DSA memory cells. Immunosuppressive memory CD4 T cells are resistant to immunosuppressive memory. CD8 T cells stimulate the production of adhesion molecules, resulting in the infiltration of leucocytes into the graft.
Targeting alloreactive T cell memory has shown some recent advancements.
-Lymphoablation
It is common practice in clinical transplantation to provide induction treatment to patients in order to alleviate the negative effects of preexisting donor-reactive immunity. Antibody-mediated lymphocyte depletion is the most widely employed induction technique, especially in patients who are extremely sensitive to the procedure or who are getting marginal grafts.
-Blockade of the costimulatory system
Belatacept, a CTLA4-Ig of the second generation, is now being utilized in clinical transplantation to reduce allograft rejection while also reducing the harmful side effects of calcineurin inhibitors.
Despite fewer side effects and greater graft survival, individuals treated with belatacept had higher rates of acute cellular rejection when compared to those treated with CNI (contrary to CNI therapy).
mai shawky
3 years ago
· Memory immune cells paly critical role in protection from infection, benefit from vaccination and tumor surveillance. However, they are strong barriers against tolerance to transplanted cells.
· These memory cells are initially formed in both animal models and human, against certain infectious or bacterial antigens identified on MHC class II molecules of APC, then due to molecular mimicry between allogenic Ag in graft and the original Ag against which the memory cells are preformed, those memory cells represent a threat against the graft with rapid and intense immune response (heterologous immunity).
· In human, these memory cells also formed due to previous sensitization as (retransplantation, pregnancy or previous transfusion). Prolonged stay on dialysis and Vit D deficiency increase risk of formation of alloreactive T cells.
· In human, only memory T cells from sensitization represent risk of AR and worse graft outcome. However, those formed against EBV infection not affect graft outcome.
· The memory T cells either:
o Central present in lymphoid tissues.
o Circulating T memory.
· Unfortunately, those memory cells are activated by lower threshold or concentration of encountered Ag. Cytotoxic memory CD 8 cells are the dominator cells in inducing graft damage and loss, but it depends on signaling and activation from CD4 cells.
· In addition, T memory cells are not affected by lymph-depletion therapy than naiive T cell. They are less susceptible to induction with ATG or alemtuzumab ( monoclonal Ab against CD52 presented on both B and T cells).
· Belatcept (CTLA4 Ig), co-stimulation blockade between CD28 :B7, used to minimize exposure and toxicity of CNI. However, it is associated with higher rejection rate that can be attributed to its minimal effect on memory cells (less reactive to co-stimulation signals).
· Conflicting results from animal studies, which found that no difference in graft outcome according to presence of memory T cells or even they are required for graft tolerance and so memory T cell targeted therapy may decrease tolerance.
· Although, there is established evidence that memory T cells accelerate allograft rejection, many factors make the implementation of detected memory cells prior to transplantation and its reflection on immunosuppressive regimen individualization much more difficult as:
– The data from exclusive animal studies can not be applied to human.
– The effect of memory cells differ according to its origin (central or circulating).
– The lab analysis to detect them depend on identification of many cytokines (difficult and expensive).
– Just detection of memory cell in peripheral circulation (not tissue resident cells).
– Other co=existing factors as preformed DSA, cold ischemia time may contribute to AR and final graft outcome.
Q. I would like to ask about the appropriate method of summarizing an article, it should include all details or just the clinically applied points? for example, I do not read or take into consideration the types of expressed receptors on different types of cells?
Reem Younis
3 years ago
-Memory T cells are characterized by their low activation threshold, robust effector functions,and resistance to immunosuppression and costimulation blockade. They reside in and recirculate through peripheral non-lymphoid tissues. -They represent an essential element of the allograft rejection process and a major barrier to tolerance induction in clinical transplantation.
– transplant patients can be sensitized from exposures to alloantigens such as previous transplants, pregnancies, and blood transfusions.
– sensitized patients exhibiting high titers of allospecific antibodies display memory T cells recognizing alloantigens indirectly as donor peptides–self-MHC
complexes.
-The accumulation of alloreactive memory T cells may be influenced by the end-stage organ disease or treatment common in transplant candidates.
-Prolonged exposure to dialysis increases the risk of developing alloreactive memory T Cells,and low serum levels of 25-OH-vitamin D in dialysis patients correlate with the frequency of alloreactive memory T cells independent of age, gender, previous transplants, or time on dialysis.
-Memory T cells have been traditionally divided into two: Central memory T cells (Tcm) and effector memory T cells (Tem).
-CD4+CXCR5hi follicular helper (Tfh) cells are memory T cells relevant to transplantation that reside in B cell follicles within secondary lymphoid organs and are essential for optimal B cell responses and antibody generation.
-Memory CD4+ T cells provide help for the robust activation of donor-reactive
effector CD8+ T cells which are the main driving force behind allograft rejection facilitated by memory CD4+ T cells in some experiments.
– Memory CD4+ T cells are resistant to immunosuppression and can provide help
for the generation of DSA leading to alloantibody-mediated graft injury.
-Gamma interferon (IFNγ) secretion by memory helper T cells is required for de novo DSA generation.
– Early direct contact of circulating memory CD8+ T cells with donor endothelium upregulates the expression of adhesion molecules and chemokines thus facilitating infiltration of recipient leukocytes into the graft.
– Memory CD8+ T cells inside the graft proliferate extensively, upregulate the expression of ICOS, and secrete IFNγ in an ICOS-dependent manner.
-Increasing graft cold ischemia storage time enhanced effector functions of
endogenous memory CD8+ T cells.
– The presence of memory T cells pretransplantation has been associated
with an increased risk for acute rejection of kidney transplants.
– Memory T cells may demonstrate regulatory capacity and suppress
deleterious pro-inflammatory immune responses.
-Antibody-mediated lymphocyte depletion is the most commonly used induction strategy, particularly in highly sensitized patients and in patients receiving marginal grafts.
-Memory T cells are the primary targets of induction therapies, they are less susceptible to depletion than naïve T cells.
-T cells with an effector/memory phenotype are detectable after anti-CD52 mAb or ATG induction and are associated with acute rejection episodes.
-The efficiency of memory CD4+ T cell depletion is generally lower than that of
CD8+ T cells . Depletion of residual CD4+ T cells severely impairs the recovery of memory CD8+ T cells after ATG treatment.
-Alefacept, a fusion protein combining the extracellular domain
of LFA-3 with constant regions of human IgG1, selectively depletes
CD45RO+ effector/memory T cells . Alefacept is used for the treatment of severe psoriasis and is showing promise for targeting alloreactive effector/memory T cells in solid organ and bone marrow transplantation.
-Belatacept, the second generation of CTLA4-Ig, is currently used in clinical transplantation to prevent allograft rejection and minimize the toxic side effects of calcineurin inhibitors but patients have higher rates of acute cellular
rejection compared to CNI treatment.
– Memory T cells are account for some belatacept-resistant rejection episodes.
-The sensitivity of memory T cells to immunosuppression is dependent on its origin.
-Preventing memory T cell entrance into graft tissue should improve transplant outcome, by the attempts to neutralize chemokines or chemokine receptors such as CCR5 or CXCR3.
-Reagents blocking LFA-1 (leukocyte function-associated antigen-1, an αLβ2 integrin) and VLA-4 (very late antigen-4, an α4β1 integrin) have been demonstrated to prolong allograft survival in experimental transplantation. Conclusion:
– The diagnostics of T cell allosensitization in transplant candidates is problematic.
-Memory T cells in humans are only in peripheral blood. So far, there is
no information on pathogenicity of tissue-resident alloreactive
memory T cells.
-Memory T cell susceptibility to immunosuppression may depend on their origins.
Sahar elkharraz
3 years ago
this Article focus on characteristic features of reactivation and function of memory cell against graft and also to shed light on strategies for deleting and suppressing memory T cell to improve outcome of survival graft.
Basic Biology of alloreactive memory T cell: Experimental Study done on rodents shows in absence of exposure to previous antigen 10% of these memory T cell react to allogen MHC molecules in vitro these cell called endogenous or natural alloreactive memory T cell which recognise intact allogenic MHC molecule through direct alloreactive pathway. These cells may generated from previous exposure to bacteria & environmental Ag present in MHC molecule which mimic complexes formed by allogenic MHC molecule bound to other peptide. this immunity called heterologous immunity. this heterogeneous immunity develops in human & non human primates due to previous exposure to infective environment and pro inflammatory agents during development. E.g. exposure to EBV infection HLA B8 individuals become sensitised to allo MHC molecule HLA B 4402 and this due to adherence to viral and parasitic peptides. in laboratory rodent has direct sensitisation with skills allograft due to appearances donor reactive memory T cell. In human transplant patients can be sensitised to alloantigen due to previous exposure to transplant/ pregnancy and blood transfusion. until now high titer of allospecific antibody of memory T cell seen in sensitised patients.
accumulation of alloreactive memory cells are may be increased by end organ disease or due to immunosuppressive agents example long duration of dialysis are risk for increase alloreactive memory T cell. Also low vitamin D on dialysis patients are risk for formation of reactive memory cells.
Location of memory T cell:
divided into 1/ central memory T cell 2/ effector memory T cell
central memory T cell express lymphoid markers CCR7 & CD 621. effector memory T cell promote migration to peripheral tissue.
In human some memory T cell differentiated effector memory T cell express native T cell. this cell located in peripheral tissue and not circulating. Trm cell express early activation markers CD69 & a EB7 integrin CD 103 along with number of tissue specific chemkine receptor. Trm cell play important role in host protection against infection.
Another type of memory T cell in relation to transplant is CD4 CXCR5 follicular with secondary lymphoid organ. this cell are essential for optimal B cell response and antibody generation . Trm cell are hard to control compare to circulating memory T cell.
Low activation threshold & resistance to conventional costimulating blockade:
Ability of memory T cell to response to lower stimulate antigen and this process important for host defence.
Donor reactive memory T cell can induce allograft rejection despite interruption of essential costimulation pathway CD28 / CD80/ CD86 & CD40 / CD15.
Role of allograft rejection:
CD4 & CD8 memory T cell may lead to allograft rejection in different mechanism.
depletion & suppression of CD8 T cell has significant effects in extend allograft survival. Memory CD4 T cell are hard to control by immunosuppressive agents and can lead to generation of DSA which lead to allantibody mediated graft injury.
recent study in mouse model of heart transplant identify drug to control CD4 independent DSA generation by memory T cell; first gamma interferon secretion by helper T cell is required for de novo DSA generation. second CD40 independent helper function of donor reactive memory CD4 T cell. heart allograft rejection were markedly inhibited by natural B cell activating factors & proliferation induced cytokines & differentiation.
Increase graft cold ischemic promote activation of memory CD8 T cell which lead to rejection.
Influence of memory T cell in allograft tolerance.
presence of memory T cell pretransplant are associated with poor outcome of graft. however presence of EBV / CMV specific memory T cell has not associated with poor outcome of graft.
recent development in targeting alloreactive T cell memory.
Lymphoablation:
it’s used in induction therapy in kidney transplant against donor reactive immunity especially in sensitised patients.
Lymphoablation are target against effector memory T cell.
it’s able to control memory T cell expansion and significant extend heart graft survival in sensitised patients.
alefacept fusion protein which are used in treatment of psoriasis & it may use in future targeting against alloreactive effector memory t cell in organ transplant & bone marrow transplant.
Costimultary blocked:
Belatacept second generation of CTLA4 Ig is used as immunosuppressive agents to prevent allograft rejection & reducing side effects of calcinurine inhibitors but may lead to acute cellular rejection.
Limiting trafficking of alloreactive memory T cell:
show that treatment with Anti leukocyte function associated antigen 1 ( LFA-1) & Anti very late antigen-4 (VLA-4) prolong graft survival in experimental study.
another study treatment with anti LFS-1 inhibit early infiltration of endogenous donor reactive memory CD8 T cell and improve outcome of graft.
Mohamed Mohamed
3 years ago
Week 1 Journal club IV. Role of Memory T Cells in Allograft Rejection and Tolerance Introduction The importance of this article comes from the fact that in spite of documented harmful effects of memory T cells in transplantation, the potential impact of such cells is mostly neglected while choosing treatment regimens. Some of the characteristics of memory T cells include: – Essential elements of allograft rejection process – Major barrier to tolerance induction in transplant practice – Commonly associated with poor graft outcome – Low activation threshold (dangerous in transplant settings) – Robust effector functions – Resistance to conventional immunosuppression & co-stimulation blockade. – Reside in & re-circulate through peripheral non-lymphoid tissues (unlike naïve T cells). Alloreactive memory T cells are subdivided according to their origins, phenotypes, & functions: (i) High affinity alloreactive memory T cell: – appear when recipients immune system directly exposed to allogenic MHC molecules. (ii) Endogenous alloreactive memory T cells: – no previous exposure to allogenic MCH. – regularly generated through microbial infections (heterologous immunity). Origins of Alloreactive Memory T Cells: – Generated through the recognition of peptides from infectious or environmental antigens presented by self-MHC, which can mimic complexes formed by allogeneic MHC molecules bound to other peptides. – This antigen mimicry is named “heterologous immunity,” & is well documented in both humans & animal models. – For example, after an EBV infection, HLA-B8+ persons can be sensitized to the HLA-B4402 molecule through antigen mimicry due to the presentation of viral peptides. – Transplant recipients can be sensitized from exposures to alloantigens such as previous transplants, pregnancies, & blood transfusions. – Memory T cells can also homeostatically proliferate in a lymphopenic environment. – This memory T cells expansion can impair tolerance induction in transplantation. – Prolonged dialysis vintage & low levels 25-OH-vitamin D in dialysis patients are other factors that lead to expansion of alloreactive memory T. Memory T cell subsets: A. Central memory T cells(Tcm): – express lymphoid homing markers CCR7 & CD62L B. Effector memory T cells(Tem): – are CCR7−CD62L− but instead express molecules that promote migration into peripheral tissues C. Terminally differentiated effector memory T cells (Temra): – re-express naïve T cell surface marker CD45RA – downregulate expression of CCR7, CD62L, & CD28 – represent a terminal stage of effector differentiation D. Resident memory T cells(Trm): – express early activation marker CD69 & αEβ7 integrin CD103 – do not circulate (reside in peripheral tissues) – may influence transplant outcome by facilitating GVHD or allograft rejection. E. Follicular helper memory T cells(Tfh): – express CD4+CXCR5 – reside in B cell follicles within secondary lymphoid organs – essential for optimal B cell responses & antibody generation. – harder to control than circulating memory T cells (spared by antibody- mediated lymphoablation) Role in Allograft Rejection – memory CD4+ become effector cells upon reactivation. – provide help for the robust activation of donor-reactive effector CD8+ T cells.
– These effector CD8+ T cells then are the main driving force behind allograft rejection facilitated by memory CD4+ T cells.
– de novo responses by naïve T cells can be effectively controlled by current immunosuppression, but memory CD4+ T cells are resistant to these therapies leading to DSA production & graft injury.
– the presence of memory T cells pre-transplantation is associated with an increased risk for acute rejection of kidney transplants RECENT DEVELOPMENTS IN TARGETING ALLOREACTIVE T CELL MEMORY Lymphoablation – Memory T cells are the primary targets of induction therapies, but are less susceptible to depletion than naïve T cells. – Tem cells are detectable after anti-CD52 mAb or ATG induction & are associated with acute rejection episodes. – The efficiency of memory CD4+ T cell depletion is lower than that of CD8+ T cells. – Alefacept, a fusion protein combining LFA-3 IgG1, is showing promise for targeting alloreactive effector/memory T cells in SOT & BMT. – Apart from direct lymphoablation, manipulating T cell metabolic pathways may offer a promising therapeutic options. Costimulatory Blockade – Belatacept, a CTLA4-Ig, improved graft survival & reduced CNI toxicity in transplantation. – However belatacept-treated patients have higher rates of TCMR compared to CNI treatment. – Memory T cells are more resistant to CTLA4-Ig effect in animal models, so possibly pre-sensitized T account for some belatacept-resistant rejection episodes. – Increased numbers of both CD4+ & CD8+ CD28− memory T cells are associated with a poor outcome in renal & lung transplantation.
– CD57+CD4+ T cells are potential mediators of belatacept-resistant renal graft rejection, are more common in kidney failure, & express high levels of molecules & cytokines consistent with effector/memory cells (Tem).
– The sensitivity of memory T cells to immunosuppression is dependent on their origin for example central memory(Tcm) cells with a less differentiated phenotype were most sensitive to the effects of costimulatory blockade.
– The complexity of costimulatory pathways that control alloimmune responses must be considered when costimulatory blockade is used in transplantation.
– Attempts to manipulate chemokines &/or their receptors as CCR5 or CXCR3 (so as to prevent memory T cell entrance into graft tissue) didn’t improve transplant outcome because chemokine/receptor network is redundant.
– However anti-LFA-1mAbs prolonged allograft survival in animal models. CONCLUSIONS It is well established that alloreactive memory T cells accelerate allograft rejection & prevent transplant tolerance. Several factors hinder the application of emerging experimental knowledge in transplant practice: – The diagnostics of T cell allosensitization is problematic. – Heterogeneity in types & functions of memory T cells, & the need for additional tests to address this complexity – Memory T cells in humans are sampled only in peripheral blood, thus skipping tissue-resident alloreactive memory T cells. – There are great discrepancies between animal models & human transplantation. – Approximating animal models to clinical situation is needed; considering frequencies of total & donor-reactive memory T cells in different species, cold ischemia time, & the presence of DSA in recipient serum.
– This will help the development of new strategies to control memory T cells & improve transplant survival in sensitized recipients.
Tahani Ashmaig
3 years ago
This article describes the different subsets of alloreactive memory T cells involved in
transplant rejection and examine their generation, functional properties, and mechanisms of action. It also discuss strategies developed to target deleterious allospecifc memory T cells in experimental animal models and clinical settings.
INTRODUCTION:
– Immune responses against previously encountered antigens are benefcial during infections, vaccinations, and tumor surveillance. But, memory immune responses against donor antigens are associated with poor graft outcome.
– Despite well documented harmful effects of memory T cells in transplantation , the potential impact of such cells is mostly neglected while choosing treatment regimens.
– In this review, the characteristics of alloreactive memory T cells and their functions are outlined.
It also describe existing and emerging strategies designed to delete or suppress memory T cells in transplant recipients.
– It discuss future areas of investigation that may translate experimental knowledge of alloreactive memory T cells into clinical practice and thus improve transplant outcome in sensitized recipients.
BASIC BIOLOGY OF ALLOREACTIVE
MEMORY T CeLLS
Origins of Alloreactive Memory T Cells
1. Heterologous immunity:
▪︎ Is well documented in both humans and experimental animal models.
▪︎Occur through the recognition of peptides from commensal bacteria or environmental antigens presented by self-MHC, which can mimic complexes formed
by allogeneic MHC molecules bound to other peptides.
▪︎Can be seen post EBV infection in HLA-B8+ individuals
2. In laboratory mice, direct sensitization with skin allografts or spleen cell.
3. In humans, transplant patients can be sensitized from exposures to alloantigens such as previous transplants, pregnancies, and blood transfusions.
3. Generation through homeostatic proliferation in a lymphopenic environment, including potentially alloreactive and pathogenic T cells. This can impair tolerance induction to allografts.
Note:
The accumulation of alloreactive memory
T cells may be influenced by the end stage organ disease or treatment common
in transplant candidates in these conditions:
i. Prolonged exposure to dialysis
ii. Low serum levels of 25-OH-vitamin D.
Subsets of Memory T Cells:
1) Central memory T cells (Tcm) which express lymphoid homing markers CCR7 and CD62L
2) Effector memory T cells (Tem) are CCR7-CD62L- but instead express molecules that promote migration into peripheral tissues.
Location of Memory T Cells
▪︎ Terminally differentiated effector memory T cells (Temra) re-express naive T cell surface marker CD45RA, while down regulating expression of CCR7, CD62L, and CD28, and represent a terminal stage of effector differentiation.
▪︎Some T cells in peripheral tissues do not circulate and represent a distinct subset of tissue-resident memory T cells (Trm) which:
i. Play an important role in host protection against infections.
ii. May influence transplant outcome by facilitating GVHD or allograft rejection.
▪︎Another important type of memory T cells relevant to transplantation is CD4+CXCR5hi follicular helper (Tf) cells that reside in B cell follicles within secondary lymphoid organs.
▪︎ As memory T cells in secondary lymphoid and non-lymphoid peripheral tissues are spared by antibody-mediated lymphoablation Trm cells may be harder to control compared to
circulating memory T cells.
■Characteristics of memory T cells:
1) Respond to lower antigen doses with limited costimulation,
2) Can induce allograf rejection despite interruption of essential costimulatory pathways.
ROLE OF MEMORY CELLS IN ALLOGRAFT REJECTION
▪︎CD4+ & CD8+ memory T cells subsets contribute to allograf rejection through distinct mechanisms.
▪︎Memory CD4+ T cells not only become effector cells upon reactivation, but
also provide help for the robust activation of donor-reactive effector CD8+ T cells.
▪︎ Allograft rejection is mediated by effector CD8+ T cells and facilitated by memory CD4+ T cells in heart-transplanted mice.
▪︎Memory CD4+ T cells are resistant to immunosuppression therapies and can provide help for the generation of DSA leading to alloantibody-mediated
graf injury.
▪︎Gamma interferon (IFNγ) secretion by memory helper T cells is required for de novo DSA generation.
▪︎Early direct contact of circulating memory CD8+ T cells with donor
endothelium facilitate infltration of recipient leukocytes into the graft.
■INflUENCE OF MEMORY T CELLS ON ALLOGRAFT TOLERANCE
▪︎In laboratory rodents, antigen-induced rather than endogenous memory T cell
prevent transplant tolerance.
▪︎ The vast majority of tolerant animals displayed low frequencies of
donor-reactive memory T cells.
-▪︎lymphoablative approaches targeting memory T cells may interfere with allograft acceptance of certain
types of transplants.
RECENT DEVELOPMENTS IN TARGETING
ALLOREACTIVE T CELL MEMORY
1) LYMPHOABLATION
▪︎Memory T cells are less susceptible to depletion than naïve T cells (T cells with an effector/memory phenotype are detectable after anti-CD52 mAb or ATG induction)
▪︎The efciency of memory CD4+ T cell depletion is generally lower than that of
CD8+ T cells.
▪︎Alefacept, is showing promise for targeting alloreactive effector/memory T cells in solid organ and bone marrow transplantation. Most importantly, pretransplant alefacept therapy synergizes with CTLA4-Ig presumably by targeting costimulatory blockade-resistant CD8+CD2hiCD28- effector/ memory T cells.
2) Costimulatory Blockade
▪︎Belatacept-treated patients have higher rates of acute cellular
rejection compared to CNI treatment.
▪︎Terminally differentiated memory CD4+ and CD8+ T cells in humans (Temra) lose CD28 expression and become in sensitive to the lack of CD28/B7 costimulation.
▪︎Another population of CD57+CD4+ T cells as potential mediators of belatacept-resistant renal allograft rejection. These cells are more common in patients with kidney failure and it downregulate CD28.
●The sensitivity of memory T cells to immunosuppression is dependent on
their origin.
ZAHID NABI
3 years ago
In this mini review authors have focused on impact of memory T cell on transplant outcome.
A very effective and robust immune response against previously exposed antigens is essential for tumor surveillance, immunization and infections however this memory response against donor antigens becomes harmful in case of transplantation and leads to poor graft outcome.response
The authors have also explained the concept of antigenic mimicry . It is likely that these memory cells are generated through the recognition of peptides from commensal bacteria or environmental antigens presented by self-MHC, which can mimic complexes formed by allogeneic MHC molecules bound to other peptides. Such antigen mimicry is named as “heterologous immunity.
Two subsets of memory T cells are recognized.
Central memory T cells which are CCR7 and CD62L positive which reside in lymphoid tissues.
Effector memory T cells are CCR7 and CD62L negative which are in peripheral tissues.
Terminally differentiated effector memory cells re express naïve T cell markers CD45RA
Tissue resident memory T cells do not circulate and are confined to peripheral tissues. Tissue resident memory cells in both lymphoid and non-lymphoid tissue tend to be resistant to destruction by lymphoablation therapies.
Memory T cells can develop a rapid response while re encountering to very low threshold of same antigenThis response takes place even in the presence of co-stimulatory blockade.
Animal studies have shown that both CD4+ and CD8+ memory T cells contribute to allograft rejection through distinct mechanisms.
The authors also explained the concept of influence of memory T cell on allograft tolerance by saying that though memory T cells are generally viewed as pathogenic in the context of transplantation, under certain circumstances they demonstrate regulatory capacity and suppress deleterious pro-inflammatory responses.
Memory T cells are less susceptible to lymphoablation and co stimulation blockade treatment compare to naïve T cells.Memory T cells may still be detectable after induction with anti CD52 or ATG.
In conclusion It is now firmly established that alloreactive memory T cells accelerate allograft rejection and prevent transplant tolerance. However, the implementation of accumulated experimental knowledge in clinical transplantation is impeded by several factors.
1. the diagnostics of T cell allosensitization in transplant candidates is problematic.
2. Memory T cells in humans are sampled only in peripheral blood. So far, there is no information on pathogenicity of tissue-resident alloreactive memory T cells.
3. Memory T cell susceptibility to immu- nosuppression may depend on their origins
4. Finally, despite rapidly accumu- lating data on alloreactive T cell memory, the discrepancies between animal models and transplantation in human patients are profound.
manal jamid
3 years ago
Memory T cells are less susceptible to lymphoablation treatment compare to naïve T cells.
Memory T cells may still be detectable after induction with ant CD52 or ATG.
They also appear to rapidly recover after induction with these agents.
Alefacept is a drug which showing promise in selective targeting of memory T cells and may form part of future treatment approaches.
manal jamid
3 years ago
Immunological memory cells has a unique property
1. It can mount an effective immune response when the stimulus is encountered again.
This response a secondary immune response – is quicker and stronger than the primary response, It takes a smaller stimulus to trigger a secondary response and it occurs even after many years since the first exposure.
2. It has resistance to conventional immunosuppression and costimulation blockade.
Immunological memory is an important mechanism and is one of the decisive factors of successful transplantation process and a major barrier to tolerance induction .
They are currently represented by T and B lymphocytes cells. Among T lymphocytes, memory cells are categories based on their origins, phenotypes, and functions central memory ( express lymphoid homing markers CCR7 and CD62L) , effector memoryCCR7−CD62L− but instead express molecules that promote migration into peripheral tissues) tissue-resident memory( express early activation marker CD69 and αEβ7 integrin CD103 along with a number of tissue-specific chemokine receptors ,The evidence that Trm cells play an important role in transplant outcom and allograft rejection .
Memory T cells can be generated through homeostatic proliferation in a lymphopenic environment, including potentially alloreactive and pathogenic T cells, Such homeostatically expanded memory T cells can impair tolerance induction to allografts.
important type of memory T cells relevant to transplantation are CD4+CXCR5hi follicular helper (Tfh) cells that reside in B cell follicles within secondary lymphoid organs and are essential for optimal B cell responses and antibody generation .
The major cells that participating in allograft rejection are T cells it become effector cells upon reactivation, and also provide help for the strong activation of donor-reactive effector CD8+ T cells . These effector CD8+ T cells are the main driving force behind allograft rejection
Memory CD4+ T cells are resistant to current immunosuppression these and can provide help for the generation of DSA leading to alloantibody-mediated graft injury. Early direct contact of circulating memory CD8+ T cells with donor endothelium upregulates the expression of adhesion molecules and chemokines thus leading to infiltration of recipient leukocytes into the graft ,thus pre transplantation sensitization with T memory cell associated with an increased risk for acute rejection of kidney transplants .
Role of Memory T Cells in Allograft Rejection and Tolerance
This paper is a review article on memory T cells highlighting the different subtypes and their role in allograft rejection and tolerance.
Memory T cells are important in our defence against infections, responding to vaccines and in tumour surveillance, however these same cells pose the biggest barrier to solid organ transplantation.
Origins of alloreactive memory T cells
In mice models, exposure to commensal bacteria and environmental antigens leads to establishment of endogenous alloreactive memory T cells.
In humans, sensitization is through exposure to blood transfusion, pregnancy and prior transplantation.
These memory T cells can also be enhanced via homeostatic mechanisms in the lymphopenic state, end stage organ disease or its treatment and vitamin D deficiency.
Location of memory T cells
Two subsets of memory T cells are recognized.
Central memory T cells which are CCR7 and CD62L positive which reside in lymphoid tissues.
Effector memory T cells are CCR7 and CD62L negative which are in peripheral tissues.
Terminally differentiated effector memory cells re express naïve T cell markers CD45RA
Tissue resident memory T cells do not circulate and are confined to peripheral tissues.
Follicular helper T cells (Tfh) are CD4+ CXR5+ are confined to B cell follicles and play a key role in of interacting with B cells and lead to antibody production.
Tissue resident memory cells in both lymphoid and non-lymphoid tissue tend to be resistant to destruction by lymphoablation therapies.
Low activation threshold and resistance to costimulatory blockade
During T cell differentiation, memory T cells acquire the ability to mount rapid response when re -exposed to the same antigen with a very low threshold.
This response takes place even in the presence of co-stimulatory blockade.
Role in Allograft Rejection
Memory CD4+ cells are resistant to current immunosuppressive treatments, which makes them available to generate donor specific antibodies.
Cd4+ T cells are also involved in activation of CD8+ cells.
CD8+ T cells produce adhesion molecules and chemoattractant molecules when they are exposed to donor endothelial cells leading to leucocyte accumulation in the graft.
Long cold ischaemia times appear to enhance the function the activity of CD8+ cells.
Influence on Allograft tolerance
Form animal studies, it appears that endogenous derived memory cells have tolerance properties while memory T cells following antigen stimulation lack tolerance properties.
Targeting alloreactive memory T cells Lymphoablation
Memory T cells are less susceptible to lymphoablation treatment compare to naïve T cells.
Memory T cells may still be detectable after induction with ant CD52 or ATG.
They also appear to rapidly recover after induction with these agents.
Alefacept is a drug which showing promise in selective targeting of memory T cells and may form part of future treatment approaches. Costimualtion Blockade
It appears that this approach of selectively blocking costimulatory signals with CTLA4-ig is not an effective strategy in treating transplant patients, as memory cells T cells tend to be resistant to this type of blockade.
This approach also prevents and blocks the function of T regulatory T cells.
Limiting trafficking alloreactive memory T cells
This approach seems to show promise in limiting CD8+ cell infiltration of cardiac allografts and could lead to prolonged graft survival.
Candidate molecules used here include ant Leucocyte function-associated antigen-1 (LFA-1) and very late antigen-4.
In conclusion, this paper has described the different types of memory T cells highlighting their location, functions and how they participate in allograft rejection and tolerance
Abdul Rahim Khan
3 years ago
During an immune response large number of effective lymphocytes are generated but most undergo activation induced cell death- AICD. Few of them survive and give rise to memory T Cells.-Tm. Memory T cells can arise in lymphopenic environment and can affect tolerance to graft. Accumulation of Tm can also be affected by Dialysis, ESRD, low vitamin D levels.
Location of memory T cells
Central– Express CCR and CD62L
Effector– These express CCR7 and CD62L
CD4/CXCR5hi Tfh cells– important in B cell response
These cell have low threshold for activation and resist conventional co stimulatory blockade.
Role in Allograft Rejection
CD4+ provide help in activation of CD8+ cells and also become effector cells which have a important role in rejection. These cell when come in contact with donor endothelium leads to up regulated expression of adhesion molecules and chemokines so as enhancing recipient leukocytes entrance in renal graft.
Role of Memory T cells in allograft tolerance
Memory T cells are related with increased acute rejection ., T cells produced as a result of viral infections may not be related to worse outcomes. These cell may under certain circumstances may provide inflammation suppressing role and providing a lymphoalative therapy in such circumstances many have negative effect on graft acceptance.
Recent developments in targeting alloreactive T cell memory
1-Lymphoablation
Memory T cells are not destroyed by induction therapy. Combination of ATG and co stimulation can give better outcomes like Alfacept. Alfacept inhibits LFA3/CD2 interaction thus blocking T cell activation
2- Co stimulatory Blockade
-Second generation of CTLA4 like Betacept can be used to decrease graft rejection but risk of cellular rejection in increased
3- Limiting Trafficking of alloreactive memory T cells– Drugs which block LFA-1 and VLA4 have shown promising results in experimental models
Filipe prohaska Batista
3 years ago
This paper describes the role of memory T cells in the process of graft tolerance and rejection, describing new and old strategies to suppress the response of these cells in the renal graft.
Sensitization by pregnancy and blood transfusion is much discussed, but viral infections and prolonged exposure to dialysis are also factors of alloantigens.
Células T de memória envolvidas
Tcm (Central Memory T cell) – Very present in lymphoid tissue (CCR7, CD62L, CD28) with high exposure to antigen-presenting cells.
Tem (Effector Memory T cell) – These lymphocytes enter the bloodstream and have a high distribution in peripheral tissue, having exposure to circulating and soluble antigens. High binding capacity with complement proteins and formation of immune complexes.
Temra (Terminally Differentiated Effector Memory T cell) – Reexpresses naive B lymphocyte receptors after specific effector activity. It is sometimes the last stage of activity of a B lymphocyte.
Trm (Resident Memory T Cell) – Low affinity for lymphocytes and the reticuloendothelial system, but very effective local action. It fights infections and is closely related to graft-versus-host disease (GVHD) and graft rejection.
Tfh (Follicular Helper Memory T cell) – Activator of B lymphocytes in plasma cells and producer of immunoglobulins. Very present in lymphoid tissues and the reticuloendothelial system and plays an important role in B lymphocyte-mediated rejection using costimulation pathways.
Costimulation pathways
Some co-stimulation pathways such as CD28/CD80/CD86, ICOS/B7RP-1, CD134/CD134L, CD70/CD27, CD137/CD137L and CD40/CD154 may explain the maintenance of CD4 levels to guarantee immunity against infections in the transplanted individual, concomitant with a decrease in CD8 lymphocytes, increasing graft survival.
Blocking CTLA4-Ig (Belatacept) appears to be a way to minimize the B-lymphocyte-mediated response in graft rejection. The presence of pre-transplant memory T cells is associated with an increased risk of acute graft rejection, which is why the antibody-mediated lymphocyte depletion induction strategy is so popular. Thus, there is a decrease in effector memory B lymphocytes, minimizing the risk of acute rejection. Selective lymphoablation may be a promising strategy in the future.
Conclusions
T cell allosensitization is very complicated. Different phenotypes added to the inability to assess cytokines in real-time.
Memory T cells in humans are measured only in peripherical blood.
Susceptibility to T cell immunosuppression will depend on its origins.
The difference between animal and human models is colossal
*Early recognition of donor specific antibodies DSA has a feed back in pathway of transplantation and immunosuppressive medication.
Origin of all Alloreactive Memory T cells :
*Heterologous immunity developed when bacteria presented by self-MHC recognise peptides and generates memory cells.
*Previous transplant, pregnancies and blood transfusions ( alloantigens ) are recognised by
memory cells. Alloreactive memory cells also formed on long term dialysis patients.
**Location of memory cells :
*Memory T cells subsets :
1- central memory T cells ( Tcm ) which express lymphoid homing markers CCR7 and CD62L.
2- Effector memory T cells are CCR7- , CD62L-.
3- Tissue- resident memory T cells which plays an important role in host protection against infections.
4- Follicular helper ( Tfh ) cells which is important for optimal B cells response and production of antibodies.
*The ability of memory T cells to respond to low antigen dose can threaten transplant process .
*Circulating memory CD8+ T cells with donor endothelium express adhesive molecules which help in leukocytes infiltration of recipients into graft .
*Pre-transplant Memory T cells are associated with increase risk of acute rejection .
*Memory T cells have low susceptibility for depletion than naiive T cells .
*Detection of memory T cells after induction therapy associated with acute rejection.
*Alfacept is targeting alloreactive effector memory T cells in solid organ and bone marrow transplantation.
*Belatacept which prevents allograft rejection has a higher rate of acute cellular rejection.
*CD57+CD4+T cells mediate belatacept-resistant renal allograft rejection express high levels of CD2 , LFA-1 and VLA-4 and suppress CD28.
CTLA4-Ig inhibits signaling of CTLA-4 which suppress regulatory T cells.
*ICOS/B7RP-1 , CD134/CD134L , CD70/CD27 and CD137/CD 137L inhibition improve graft survival.
*Inhibition of LFA-1 mAbs pre-transplant inhibits endogenous donor-reactive memory CD8+ T cells which in sequence reflected in prolonged graft survival.
References :
1. Augustine JJ, Siu DS, Clemente MJ, Schulak JA, Heeger PS, Hricik DE. Pre- transplant IFN-gamma ELISPOTs are associated with post-transplant renal function in African American renal transplant recipients. Am J Transplant (2005) 5(8):1971–5. doi:10.1111/j.1600-
6143.2005.00958.x
2. Heeger PS, Greenspan NS, Kuhlenschmidt S, Dejelo C, Hricik DE, Schulak JA, et al. Pretransplant frequency of donor-specific, IFN-gamma-producing lymphocytes is a manifestation of immunologic memory and correlates with the risk of posttransplant rejection episodes. JImmunol (1999) 163(4):2267–75.
3. Hricik DE, Rodriguez V, Riley J, Bryan K, Tary-Lehmann M, Greenspan N, et al. Enzyme linked immunosorbent spot (ELISPOT) assay for interferon-gamma independently predicts renal function in kidney transplant recipients. Am J Transplant (2003) 3(7):878–84. doi:10.1034/j.1600-6143.2003.00132.x
4. Poggio ED, Augustine JJ, Clemente M, Danzig JM, Volokh N, Zand MS, et al. Pretransplant cellular alloimmunity as assessed by a panel of reactive T cells assay correlates with acute renal graft rejection. Transplantation (2007) 83(7):847–52. doi:10.1097/01.tp.0000258730.75137.39
5. Lombardi G, Sidhu S, Daly M, Batchelor JR, Makgoba W, Lechler RI. Are primary alloresponses truly primary? Int Immunol (1990) 2(1):9–13.
6. Benichou G, Valujskikh A, Heeger PS. Contributions of direct and indirect T cell alloreactivity during allograft rejection in mice. J Immunol (1999) 162(1):352–8.
7. Benichou G. Direct and indirect antigen recognition: the pathways to allograft immune rejection. Front Biosci (1999) 4:D476–80.
8. Lechler R, Lombardi G. Structural aspects of allorecognition. Curr Opin Immunol (1991) 3(5):715–21.
9. Mbitikon-Kobo FM, Vocanson M, Michallet MC, Tomkowiak M, Cottalorda A, Angelov GS, et al. Characterization of a CD44/CD122int memory CD8 T cell subset generated under sterile inflammatory conditions. J Immunol (2009) 182(6):3846–54. doi:10.4049/jimmunol.0802438
Memory T cells accelerate graft rejection and prevent transplant tolerance Basic biology of alloreactive memory T cells Origin: :
Heterologous immunity: memory cells are generated after recognition of peptides from commensal bacteria or environmental antigens presented by self-MHC. Transplant patients can be sensitized from exposure to alloantigens as in pregnancy, blood transfusion and previous transplant.
Can be generated through homeostatic proliferation in lymphopenic environment including potentially alloreactive and pathogenic T cells.
May be produced in end stage organ disease, for example, dialysis increases the risk of production of alloreactive memory T cells and a study showed that low vitamin D in dialysis patients correlates with frequency of alloreactive memory T cells
Location:
Central memory T cells (Tcm) express lymphoid homing markers
Effector memory T cells (Tem) express molecules promote migration to peripheral tissues.
Tissue resident memory T cells (Trm): protective against infection but Trm of recipient increase risk of allograft rejection (its role in transplant is not well addressed)
Follicular helper cells (Tfh) reside in B cell follicle in secondary lymphoid organ and important for B cell response and antibody generation.
Low activation threshold and resistant to conventional costimulatory blockade:
They respond to low antigen doses with limited costimulation making them more dangerous in transplant. Role in allograft rejection:
memory CD4 T cells become effector cells on reactivation and help in activation of CD8 T cells and help in production of DSA
memory CD4 T cells are resistant for immunosuppression
memory CD8 T cells increase expression of adhesion molecules leading to leucocyte infiltration in the graft.
Influence on allograft tolerance:
Presence of memory T cells pre transplant is associated with increased risk of acute rejection. However, some studies showed that under certain circumstances, memory T cells have regulatory capacity and decrease pro-inflammatory immune response. Recent developments in targeting alloreactive memory T cells: Lymphoablation:
antibody mediated lymphocyte depletion, used in induction in sensitized patient and when receiving marginal grafts to eliminate pre existing donor reactive immunity.
memory T cells are primary target of induction but are more resistant than naive T cells.
Several studies showed a synergistic effect between ATG lymphoablatin and costimulatory blockade
Alefacept may be used in targeting alloreactive effector and memory T cells in solid organ transplant
Regulating cell metabolic pathway through manipulating T cell homeostasis may be a therapeutic strategy.
Costimulatory blockade:
Belatacept
Used to prevent graft rejection, it blocks CD28/B7 costimulation and prevent signaling through CTLA-4.
Terminally differentiated memory CD4 & CD8 T cells become insensitive to costimulation blockade leading to accumulation of CD4 and CD8 memory T cells.
A recent study showed that CD57CD4 T cells (which are common in renal failure) are potential mediators of belatacept resistant renal graft rejection.
A study showed that sensitivity of memory T cells to immunosuppression varies according to its origin where Tcm with less differentiated phenotype were the most sensitive to costimulatory blockade.
CD40/CD154is another major costimulatory pathway attempted to be blocked but resulted in thromboembolic effects. Limiting trafficking of alloreactive memory T cells:
Attempts to neutralize chemokines and chemokine receptors didn’t meet the expectations. Limitations to target memory T cells in clinical transplantation:
The heterogenicity in phenotype and functions of memory T cells
memory T cells are sampled from peripheral blood without information about tissue resident T cells
Sensitivity of T memory cells to immunosuppression depends on its origin which can’t be traced.
Major differences between human and animal models.
Alloreactive memory T cells represent an essential element of the allograft rejection process and a major barrier to tolerance induction in clinical transplantation. This article describes the different subsets of alloreactive memory T cells involved in transplant rejection and examine their generation, functional properties, and mechanisms of action.
CD4 + and CD 8+ T cells work together in the activation of donor-reactive: generation of DSA leading to alloantibody-mediated graft injury, endothelium upregulates the expression of adhesion molecules and chemokines, secretion gamma interferon, upregulate the expression of ICOS;
Some characteristics are important in the performance of memory T cells:
1 – alloreactive memory T cells may be sensitized from exposures to alloantigens such as previous transplants, pregnancies, and blood transfusions. There are also other important situations such as: homeostatic proliferation in a lymphopenic environment, end stage organ disease or treatment common in transplant candidates;
2 – location of memory T cells in : Central X peripheral tissues (Tem and yours subset : Temra and Trm). Where the existence of peripheral T cells may influence transplant outcome facilitated by GVHD or allograft rejection.
3 – Memory T cells has the ability to respond to lower antigen doses with limited costimulation, because T cell receptor and costimulatory signaling cascades are adjusted to ensure rapid activation of high magnitude.
4 – Memory T cells are less susceptible to antibody-mediated lymphocyte depletion, as well as costimulatory blockade with Belacept. But, assays demonstrated that the sensitivity of memory T cells to immunosuppression is dependent on their origin and others costimulatorys are involved, enabling the action of immunosuppressants such as: tacrolimus, mAb inhibits proliferation and others
Despite the information above, there are impediments to implementing protocols based on existing experimental knowledge, due to the following factors:
1 – the diagnostics of T cell allosensitization in transplant candidates is problematic, because to heterogeneity in phenotype and functions of memory T cells, complementary tests will be required including analyses of cytokine producing, cytotoxic, and follicular helper T cells ;
2 – memory T cells in humans are sampled only in peripheral blood. So far, there is no information on pathogenicity of tissue-resident alloreactive memory T cells;
3 – memory T cell susceptibility to immu[1]nosuppression may depend on their origins. As immunological histories of individuals are difficult to trace, the situation may arise when patients with similar T cell memory profile require distinct treatment strategies
Origin of alloreactive memory T cells:
In mice, memory T cells constitute around 5-10% of all T cells. In the absence of prior exposure to antigens, only 1-10% can react to allogeneic MHC, the source of these memory cells is infection and exposure to environmental antigens ( heterologous immunity).
Memory T cells can also be generated through homeostatic proliferation in a lymphopenic environment and can impair tolerance to allografts.
The accumulation of these memory cells can be affected by the end-organ disease such as in patients with ESRD, prolonged exposure to dialysis & the low level of 25 OH-vitamin D in these patients lead to the development of memory cells.
Location of memory T cells:
central memory T cells: express CCR7 and CD62L. ( harder to control)
Effector memory T cells: express CCR7, CD62L.
CD4+CXCR5hi Tfh cells: resides in B cell follicles and are essential for B cells responses and antibody generation.
Memory T cells are characterized by a low activation threshold and resistance to costimulatory blockade and this results in the ability of memory T cells to respond to lower antigen doses with limited costimulation.
Role in allograft rejection:
Upon activation of memory CD4+ T cells, they become effector cells & also provide help for the activation process of CD8+ T cells. These effector CD8+ T cells are the main driving force for rejection. Early direct contact of these cells with donor endothelium upregulates the expression of adhesion molecules and chemokines thus facilitating infiltration of the recipient leukocytes into the graft.
Memory CD4+ T cells are resistant to immunosuppressive medications and can provide help for DSA formation & ABMR.
Influence of memory T cells on allograft tolerance:
The presence of memory T cells pretransplantation has been associated with an increased risk of acute rejection, however, there is no indication that the presence of heterologous immunity( such as EBV, CMV-specific memory T cells) correlates with worse graft outcomes.
Under certain circumstances, memory T cells show a regulatory effect and suppress the pro-inflammatory immune response and there is concern about the lymphoablative approaches targeting memory T cells may interfere with allograft acceptance of certain types of transplants.
Recent developments in targeting alloreactive T cell memory
Lymphoablation: ATG, Alemtuzumab- less effective. Alefacept a recombinant dimeric fusion protein inhibits LFA3/ CD2 interaction and thus inhibits T cells activation, selectively depletes memory T cells, currently used for the treatment of psoriasis.
costimulatory blockade: Belatacept second generation of CTLA4-Ig is currently used to prevent rejection and minimize the toxic effect of CNI, but there is an increased incidence of cellular rejection compared to CNI as memory cells are more resistant to the effect of CTLA4-Ig and terminally differentiated memory CD4+, CD8+ T cells lose CD28 expression.
Limiting trafficking of alloreactive memory T cells: reagents blocking LFA-1 & VLA-4 have been demonstrated to prolong allograft survival in experiments.
Memory T cells a component of immune system that requires minimal threshold for activation, mounts strong immune response upon re-exposure to the same antigen. They are also resistant to standard immune-suppression and co-stimulation blockade. This later effects are dangerous in transplantation
Basic Biology of allo-reactive memory T cells ;
Origin of allo-reactive memory T cells ;
Antigen mimicry or heterologous immunity 8.
Haemostatic proliferation in a lymphopenic condition 13-15
Location of memory T cells ;
Central memory T cell (Tcm) ; express CCR7, CD26L
Effector memory T cells (Tem) ; express proteins which enhances migration into peripheral tissues 20-30
Terminally differentiated effector memory T cells(T temra) ; re-express naive T cell surface markers and down regulate Tcm 21-25
Tissue-resident memory T cells(Trm); they dont circulate and provide defense against infection 26-29-32
Follicular helper (Tfh) cells CD4+CXR5 ;reside in the B cells and important in B responses 33.
Low Activation of Threshold and Resistance to Conventional Co-stimulatory Blockade ;
Memory T cells react to minimal antigen re-exposure being presented by non-professional APC36 -38
Donor-reactive memory can still cause rejection in the presence of co-stimuation blockades 39-43.
Contribution of memory T cells to allograft rejection & tolerances ;
Role in allograft rejection ;
Memory CD4+ provide helps for massive activation of effector CD8+ cells 40.
Resistance to current immunosuppression & DSA formation 40,44
Up-regulation of adhesion molecules and chemo-kines 47,48
Up-regulation of ICOS & secretion of TNF-alfa 49 ,50
Influence of Memory T cells on Allograft Tolerance ;
In animal model following conditional therapy and withdrawal of immunosuppression, 30 % of treated Monkeys rejected their allograft immediately 61. Most of the tolerant animals showed low frequencies of donor-reactive memory T cells 61
Beside the pathogenic properties of memory T cells , they can display regulatory functions and suppress the harmful effects of pro-inflammatory cytokines.
Infiltration of lung allograft by Tc memory cells in early post-transplant is essential for the graft acceptance 63. This may question the use of lympho-ablative therapy targeting Tc memory cells in acceptances of some types of allografts.
Recent Developments in Targeting Alloreactive T cell memory ;
Lymphoablation ;
Memory T cells are not destroyed by induction therapy like the naive T cells 70-73
In rodents, the recovers rapidly after ATG induction
Combination of ATG lympho-ablation and costimualtion gives better results .e.g. Alefacept 83-85
Reguation of T Cell metabolic pathways is another new concept rather than direct ATG lymphoablation 96
Costimuatory Blockade ;
Belatacept ; is CTLA4-Ig used to reduce side effects associated with CNIs and prevent rejection 97.
Risk of acute rejection is high 98,99 and this may be due to pre-sensitised memory T cells.
CD40/CD154 ; is another costimuation but it was not favored due thrombo-embolic side effects of anti-CD154 122.
Inhibition or genetic lack of ICOS/B7RP-1, CD134/CD134L, CD70/CD27 , or CD137/137L improved allograft survival.
Limiting Trafficking of allo-reactive Memory T cells ; Anti-LFA-1(Leukocytes Function Associated Antigen-1) and anti-VLA-4( Very Late Antigen 4) were associated with improve graft survival in experimental models 133.
Concluding Remarks ; some challenges in transplantation includes
Problems with diagnosis of T cell allosensitization because T cells are heterogeneous, with different functions.
Memory T cells are always obtained from peripheral blood and no information about Trm
Sensitivity of the memory T cells to immunosuppression depend on their origin
Huge differences between animal models and human experiments in transplantation.
Role of memory T cells in allograft rejection and tolerance.
Rapid response of Memory T cells is considered double edged sword as its beneficial when occurred with infection, vaccination and tumor surveillance , but when response occurred due to donor antigen so, its associated with high risk of rejection and poor graft outcome. BASIC BIOLOGY OF ALLOREACTIVE MEMORY T CELLS. Origins of Alloreactive Memory T Cells:
Memory T cells can be generated after recognition of protein peptides of pathogens(viral, bacterial, etc.),which structurally resembling the allogenic MHC molecule which is called “heterologous immunity,”
For example, following an EBV infection, HLA-B8+ individuals is sensitized to the allo-MHC molecule HLA-B4402 through antigen mimicry .
The transplant patients can be sensitized from exposures to alloantigen such as previous transplants, pregnancies, and blood transfusions so they have high titer of memory T cells and also Memory T cells increasing with patients on dialysis for long period. Location of Memory T Cells:
Central memory T cells (Tcm) :express markers CCR7 and CD62L and effector memory T cells (Tem) in peripheral tissue.
Tissue-resident memory T cells (Trm)which are T cells in peripheral tissues do not circulate (so, its harder to control compared to circulating memory T cells)and play an important role in host protection against infections, but has a role in transplant outcome by facilitating GVHD or allograft rejection.
The follicular helper (Tfh) cells located in B cell follicles within secondary lymphoid organs and are essential B cell responses and antibody generation . Low Activation Threshold and Resistance to Conventional Costimulatory Blockade:
Memory T cells are programmed during differentiation to be rapid active of high level with antigen reencounter and respond to lower antigenicity which is good in body defense but this induce graft rejection in transplant despite using costimulatory blockade. CONTRIBUTION OF MEMORY T CELLS TO ALLOGRAFT REJECTION AND TOLERANCE:
Memory CD 4 T cell has a role in reactivation and also help donor-reactive effector CD8+ T cells which play a major role in allograft rejection so decreasing or depleting of effector CD8+ T increase graft survival.
CD 4 T cell help for the generation of DSA leading to alloantibody-mediated graft injury and unfortunately resistant to current immunosuppression.
Direct contact of circulating memory CD8+ T cells with donor endothelium upregulates the expression of adhesion molecules and chemokines thus facilitating infiltration of recipient leukocytes into the graft which increase risk of rejection and prolonged cold ischemia aggravate this cascade. Influence of Memory T Cells on Allograft Tolerance.
The presence of memory T cells pre-transplantation are associated with an increased risk for acute rejection of kidney transplant but “heterologous immunity” in transplant recipients doesn’t correlates with worse graft outcomes ,so lymph ablative approaches targeting memory T cells may interfere with allograft acceptance of certain types of transplants. RECENT DEVELOPMENTS IN TARGETING ALLOREACTIVE T CELL MEMORY Lymphoablation:
One of the most important strategy in sensitized recipients is induction therapy by ATG or alemtuzumab which is directed mainly to Memory T cells but its efficacy is less than naïve T cell.
Alefacept, a fusion protein which binds to CD2which is expressed on effector/memory T cells and depleting them so its used for targeting
costimulatory blockade-resistant CD8+CD2hiCD28 effector/memory T cells as coeffect for CTLA4-Ig . Costimulatory Blockade
Belatacept, a second generation of CTLA4-Ig, is currently used in clinical transplantation to prevent allograft rejection but terminally differentiated memory CD4+ and CD8+ T cells in humans (Temra) lose CD28 expression so become insensitive to CTLA4-Ig due to the lack of CD28/B7 co-stimulation. Limiting Trafficking of Alloreactive Memory T Cells.
By using the integrin blockade like anti-LFA-1 or anti-VLA-4 blocking mAbs especially with costimulatory blockade-resistant rejection by memory CD8+ T but still need further studies.
In the modern era of potent immunosuppression, acute rejection remains a great obstacle for the short and long term preservation of kidney function.
The preformed memory T cells against allograft antigens are associated with increased risk of acute rejection and allograft failure.
Memory T cells are well known or their low activation threshold, aggressive inflammatory functions, and resistance to conventional immunosuppression and co-stimulation blockade.
Memory T cells have protective effects against infection and tumors. They are also responsible for long term protection against infection through vaccination. This protective effect against infection or malignancy is considered detrimental in the setting of transplantation. Activation of memory T cells is associated with T cell mediated activation of B cells with subsequent production of donor specific antibodies and eventually acute antibody mediated rejection. AMR is commonly associated with poor graft outcome.
Memory T cells are classically divided into two major groups.
Central memory T cells (Tcm) markers CCR7 and CD62L, whereas effector memory T cells (Tem) are CCR7−CD62L− .T em express molecules that promote migration into peripheral tissues. Another type of T cells in humans called terminally differentiated effector memory T cells (Temra) express naive T cell surface marker CD45RA, while downregulating expression of CCR7, CD62L, and CD28, and represent a terminal stage of effector differentiation.
Several studies during the past decade have investigated the role of CD4+ and CD8+ memory T cells in acute rejection and showed that these subsets contribute to allograft. Indeed, memory CD4+ T cells not only become effector cells upon reactivation, but also provide help for the robust activation of donor-reactive effector CD8+ T cells.
Current immunosuppression can efficiently control de novo responses by naïve T cells, however memory CD4+ T cells are resistant to immunosuppression and can activate B cell response and generation of DSA leading to alloantibody-mediated graft injury.
T memory cells can demonstrate regulatory capacity and suppress deleterious pro-inflammatory immune responses, although memory T cells are generally viewed as pathogenic in the context of transplantation.
Therapies that was used to target memory cells include lymphoablation, costimulatory blockade and integrin blockade.
The most commonly used induction regimen in high risk patients include drugs that aim to block t cell response. Antibody-mediated lymphocyte depletion of t cells include monoclonal and polyclonal antibodies.
Although memory T cells are the primary targets of induction therapies, they are less susceptible to depletion than naïve T cells. The efficiency of memory CD4+ T cell depletion is generally lower than that of CD8+ T cells. Additional depletion of residual CD4+ T cells severely impairs the recovery of memory CD8+ T cells after ATG treatment.
Costimulatory pathways have been also the target of blockade, as Belatacept does.
Belatacept, B7 inhibitor, is currently used in clinical transplantation to prevent allograft rejection and minimize nephrotoxic effect of CNI. Memory T cells are more resistant to the effects of CTLA4-Ig in animal transplantation models,that’s why patients treated with belatacept have higher rates of acute cellular rejection compared to CNI treated group,but have reduced side effects and improved graft survival. it is possible that presensitized T cells could account for some belatacept-resistant rejection episodes.
In addition to blocking CD28/B7 costimulation, CTLA4-Ig also prevents signaling through CTLA-4, which can have negative effects on generation and functions of regulatory T cells (Tregs).
Another way for blockade of T cell activation is the use of integrin blockade. Findings in some studies suggested that a short course of integrin blockade may be effective in controlling T cell memory while avoiding side effects of long-term treatments. Reagents blocking LFA-1 and VLA-4 have been demonstrated to prolong allograft survival in experimental transplantation.
very well demonstrated and understood
clear explanation of:
increased incidence of TCR with CTLA-4Ab despite less side effects of CNIs
relation with Tregs
Differential effect of ATG on both cells
WELLDONE
your summary is useful to the rest of the group.
Sherif Yusuf
3 years ago
Memory T cells exhibit the following criteria :
Memory cells are either B or T cells
In appearance they are identical to mature resting cells
Memory cells are formed after exposure to foreign antigen, and can persists for decades after primary exposure
They are very sensitive and react rapidly to previously encountered antigen than naive cells
They are responsible for secondary immune Reponses with production of powerful high affinity antibodies
Play very important rule in protection against invading pathogens especially if patient is under immunosuppression
Types of memory T cells
Tissue resident memory T cells (Trm): hidden in the tissues and do not circulate, resistant to lymphoablation
Central memory T cells (Tcm)
Effector memory T cells (Tem) they migrate to peripheral tissue
Terminally differentiated effector memory T cells (Temra)
Follicular helper (Tfh) cells that are responsible for B cell activation and antibody production
Memory cells to HLA antigens may be preformed due to pregnancy, previous blood transfusions or previous transplantations, or may arise after transplantation.
Why memory cells are important in renal transplantation
1. Memory cells has lower activation threshold and persist for long time when compared to naive cells
2. Memory cells are resistant to costimulation signals that mean they require lower costimulatory signals for being recalled
3. Memory cells are resistant to regulatory T cells
4. They are not suppressed by conventional immunosuppressive drugs
5. Highly resistance to induction of tolerance
thus alloreactive memory cells constitute a significant challenge when transplanting a foreign graft.
Curently transplantation is depending on negative cross match between donor and recipient and HLA matching , but this may be misleading as it ignores the rule of memory cells in future graft rejection. thus traditional immunosuppression may has good effect on short term graft survival, but long term graft survival may be lower due to memory cells
Mechanism of rejection by memory cells
Rejection occurs either due to Alloantigen-dependent or alloantigen-independent factors (tissue injury such as ischemic injury leading to upregulation of expression of adhesion molecules, or shedding of intact HLA )
Either Allo-antigen independent or dependent factors activate the immune response in the following way:
1- Donor-reactive memory CD4+ T cells are 2 types T helper 1 that activate macrophage leading to delayed type hypersensitivity and T helper 2 that provide help to B cells leading to trasnformation of B cells to plasma cells that produce DSA.
2- Alloreactive CD8-positive T cells that produce cell-mediated cytotoxicity (kill the cell or induced apoptosis)
Two-signal are required for T cell activation
· Signal 1 occur when antigen peptide- MHC complex located on APC is attached to TCR
· Signal 2 occur when one or more TCR antigens (CD28, CTLA-4) interacts with its specific legand in APC (B7-1, B7-2). this is called costimulation, CD28 stimulate, while CTLA-4 supress T cells
Interventions that target memory T cells
1- Lymphoablation by depleting T cells using ATG, ATG cause depletion of T cells, although ATG induced lymphopenia triger generation of alloreactive memory T cells, but it was found that ATG significantly increase T regulatory cells which supress memory T cells, So better survival of graft was obtained by ATG induction
2- Co-stimulation blockade , Abatacept (CTLA4-Ig) is still under trial but it was found that the use of abatacept is associated with inhibition of T helper 1 and not T helper 2, leading to decrease in the incidence of acute rejection, but chronic rejection still occurs
Belatacept (a high affenity variant CTLA4-Ig), has been developed with more immunosuppressive effect
good you mentioned there are both memory T and B cells.
Ibrahim Omar
3 years ago
Role of memory T-cells in organ transplantation :
Basic biology :
1- Memory T-cells are a small subgroup of T- lymphocytes. However, unlike
their native counterparts, memory T- cells reside and recirculate through non-lymphoid tissues.
2- They are classified into different categories, based on their origin, phenotype and function
3- They are generated by previous allo-antigen exposure as with previous blood transfusion, organ transplantation, pregnancy or previous infections.
Location : there are 2 main types.
1- Central : they are expressing CCR7 and CD62L.
2- Effector : they are expressing molecules that promote migration into peripheral tissues.
Role of memory T-cells in allograft rejection and tolerance :
these cells are largely involved in accelerating allograft rejection and prevention of immune tolerance, which is the hopeful current and future target in the field of solid organ transplantation. Currently, memory T-cells are the target of many therapeutic approaches.
Recent developments in targeting allo-reactive T- cells :
1- Lymphoablation : By induction therapy. However, memory T- cells are less susceptible to treatment than naive T-cells.
2- Co-stimulation blockade : By Belatacept. there was a reported decrease in side effects of maintenance immunosuppression but unfortunately, there was an increase in the incidence of acute cellular rejection.
3- Limiting trafficking by a short course of integrin blockade.
Barriers against implementation of current data in clinical transplantation :
1- Diagnostics of T- cell allosensitization is problematic due to significant variations in memory T- cells functions and phenotypes. Therefore, complementary tests are needed and the resulting information is complex.
2- Memory T-cells are sampled only in peripheral blood, so no information on pathogenicity of tissue-resident cells is clearly available.
3- The discrepancies between animal transplantation models and transplantation in human are profound.
Memory b cells, alloantibodies and innate immune response affects the transplant outcome. Also, memory T cells have harmful effect on transplant but their impact is neglected in choosing treatment regimens
.
Transplant patients can be sensitized from exposures to alloantigens such as previous transplants, pregnancies, and blood transfusions
Location of Memory T Cells and types
There is various types of memory T cells, including
Tissue resident memory T cells (Trm): Do not circulate in blood -indicated by their name- express early activation marker CD69 and αEβ7 integrin CD103 along with a number of tissue-specific chemokine receptor. They are spared by antibody mediated lymphoablation and harder to control than circulating memory T cells. Trm cells of the donor facilitate GVHD and from recepirnt facilitate allograft rejection.
Central memory T cells (Tcm) express lymphoid homing markers CCR7 and CD62L, whereas effector memory T cells (Tem) are CCR7−CD62L− but instead express molecules that promote migration into peripheral tissues
terminally differentiated effector memory T cells (Temra) reexpress naive T cell surface marker CD45RA, while downregulating expression of CCR7, CD62L, and CD28, and represent a terminal stage of effector differentiation
Another important type of memory T cells relevant to transplantation is CD4+CXCR5hi follicular helper (Tfh) cells that reside in B cell follicles within secondary lymphoid organs and are essential for optimal B cell responses and antibody generation
Low Activation Threshold and Resistance to Conventional Costimulatory Blockade
Memory T cell are responsible for the rapid activation and high response once antigen is encountered. This is an important process for immunological defenses but in transplant patients it makes alloreactive memory T cells dangerous to the transplant.
Numerous studies in animal models have demonstrated that donor-reactive memory T cells can induce allograft rejection despite interruption of essential costimulatory pathways, CD28/CD80/CD86 and CD40/CD154
CONTRIBUTION OF MEMORY T CELLS TO ALLOGRAFT REJECTION AND TOLERANCE
Role in Allograft Rejection
Memory CD4+ T cells become effector cells once reactivated and also cause enormous activation of donor reactive effectors CD8+ T cells – which then constitute as the main force for allograft rejection-. The main problem is, unloke naïve T cells, these CD4+ T cells are resistant to conventional immunosupressants and lead to the generation of DSA and alloantibody mediated graft injury.
Influence of Memory T Cells on Allograft Tolerance
presence of memory T cells pretransplantation has been associated with an increased risk for acute rejection of kidney transplants. However, while EBV- and CMV-specific memory T cells displaying alloreactivity have been detected in human transplant recipients, so far there is no indication that the presence of “heterologous immunity” in transplant recipients correlates with worse graft outcomes.
RECENT DEVELOPMENTS IN TARGETING ALLOREACTIVE T CELL MEMORY
Lymphoablation
Induction therapy is widely used in clinical transplantation to overcome the deleterious effects of preexisting donor-reactive immunity. Antibody-mediated lymphocyte depletion is most commonly used induction strategy, particularly in highly sensitized patients and in patients receiving marginal grafts
Alefacept, a fusion protein combining extracellular domain of LFA-3 with constant regions of human IgG1. Alefacept is currently being used in clinic for the treatment of severe psoriasis and is showing promise for targeting alloreactive effector/memory T cells in solid organ and bone marrow transplantation
Costimulatory Blockade
Belatacept, a second generation of CTLA4-Ig, is currently used in clinical transplantation to prevent allograft rejection and minimize the toxic side effects of calcineurin inhibitors, bit still belatacept treated patients have higher rates of acute cellular rejection compared to CNI treatment.
CONCLUDING REMARKS
The diagnostics of T cell allosensitization in transplant candidates is problematic. Due to heterogeneity in phenotype and functions of memory T cells, complementary tests will be required including analyses of cytokine producing, cytotoxic, and follicular helper T cells
Memory T cells in humans are sampled only in peripheral blood. So far, there is no information on pathogenicity of tissue-resident alloreactive memory T cells.
Memory T cell susceptibility to immunosuppression may depend on their origins. As immunological histories of individuals are difficult to trace, the situation may arise when patients with similar T cell memory profile require distinct treatment strategies.
Despite rapidly accumulating data on alloreactive T cell memory, the discrepancies between animal models and transplantation in human patients are profound.
well understood final summary is efficiantly clarifying. thankyou
MICHAEL Farag
3 years ago
Role-of-Memory-T-Cells-in-Allograft-Rejection-and-Tolerance
Alloreactive memory T cells represent an essential element of the allograft rejection process and a major barrier to tolerance induction in clinical transplantation. This article describes the different subsets of alloreactive memory T cells involved in transplant rejection and examine their generation, functional properties, and mechanisms of action.
Basic biology OF alloreactive memory T cells Origins of Alloreactive Memory T Cells In humans, transplant patients can be sensitized from exposures to alloantigens such as previous transplants, pregnancies, and blood transfusions. Until now, only memory T cells recognizing intact alloantigens directly have been reported. Yet, it is probable that sensitized patients exhibiting high titers of allospecific antibodies display memory T cells recognizing alloantigens indirectly as donor peptides–self-MHC complexes. Memory T cells can also be generated through homeostatic proliferation in a lymphopenic environment, including potentially alloreactive and pathogenic T cells. Such homeostatically expanded memory T cells can impair tolerance induction to allografts. The accumulation of alloreactive memory T cells may be influenced by the end stage organ disease or treatment common in transplant candidates. For example, prolonged exposure to dialysis increases the risk of developing alloreactive memory T cells. In addition, low serum levels of 25-OH-vitamin D in dialysis patients correlates with the frequency of alloreactive memory T cells independent of age, gender, previous transplants, or time on dialysis. Location and types of Memory T Cells Memory T cells have been traditionally divided into two major subsets with largely overlapping functions but distinct trafficking patterns – Central memory T cells (Tcm) express lymphoid homing markers CCR7 and CD62L. – effector memory T cells (Tem) are CCR7−CD62L− but instead express molecules that promote migration into peripheral tissues. – In humans, but not in mice, some memory T cells [terminally differentiated effector memory T cells (Temra)] reexpress naive T cell surface marker CD45RA, while downregulating expression of CCR7, CD62L, and CD28, and represent a terminal stage of effector differentiation – some T cells in peripheral tissues do not circulate and represent a distinct subset of tissue-resident memory T cells (Trm). Trm cells express early activation marker CD69 and αEβ7 integrin CD103 along with a number of tissue-specific chemokine receptors. There is accumulating evidence that Trm cells play an important role in host protection against infections. It is conceivable that Trm cells of both donor and recipient origins may influence transplant outcome by facilitating GVHD or allograft rejection respectively. – Another important type of memory T cells relevant to transplantation is CD4+CXCR5hi follicular helper (Tfh) cells that reside in B cell follicles within secondary lymphoid organs and are essential for optimal B cell responses and antibody generation Contribution OF memory T cells TO allograft rejection and tolerance A) Role in Allograft Rejection During the past decade, studies investigating CD4+ versus CD8+ memory T cells revealed that these subsets contribute to allograft rejection through distinct mechanisms. Indeed, memory CD4+ T cells not only become effector cells upon reactivation, but also provide help for the robust activation of donor-reactive effector CD8+ T cells. These effector CD8+ T cells then are the main driving force behind allograft rejection facilitated by memory CD4+ T cells. While de novo responses by naïve T cells can be efficiently controlled by current immunosuppression, memory CD4+ T cells are resistant to these therapies and can provide help for the generation of DSA leading to alloantibody-mediated graft injury Early direct contact of circulating memory CD8+ T cells with donor endothelium upregulates the expression of adhesion molecules and chemokines thus facilitating infiltration of recipient leukocytes into the graft. The approximation of clinical situation by increasing graft cold ischemia storage time enhanced effector functions of endogenous memory CD8+ T cells enabling them to promptly reject a cardiac allograft despite costimulatory blockade with CTLA4-Ig. B)influence of Memory T Cells on Allograft Tolerance The presence of memory T cells has been often correlated with poor outcomes in clinical transplantation. In humans, the presence of memory T cells pretransplantation has been associated with an increased risk for acute rejection of kidney transplants. However, while EBV- and CMV-specific memory T cells displaying alloreactivity have been detected in human transplant recipients, so far there is no indication that the presence of “heterologous immunity” in transplant recipients correlates with worse graft outcomes. Even though memory T cells are generally viewed as pathogenic in the context of transplantation, under certain circumstances, they demonstrate regulatory capacity and suppress deleterious pro-inflammatory immune responses Recent developments in targeting alloreactive T cell memory A) Lymphoablation Induction therapy is widely used in clinical transplantation to overcome the deleterious effects of preexisting donor-reactive immunity. Antibody-mediated lymphocyte depletion is most commonly used induction strategy, particularly in highly sensitized patients and in patients receiving marginal grafts. Although memory T cells are the primary targets of induction therapies, they are less susceptible to depletion than naïve T cells. The efficiency of memory CD4+ T cell depletion is generally lower than that of CD8+ T cells. Alefacept is currently being used in clinic for the treatment of severe psoriasis (89, 90) and is showing promise for targeting alloreactive effector/memory T cells in solid organ and bone marrow transplantation (91–95). Most importantly, pretransplant alefacept therapy synergizes with CTLA4-Ig presumably by targeting costimulatory blockade-resistant CD8+CD2hiCD28- effector/ memory T cells B) Costimulatory Blockade Belatacept, a second generation of CTLA4-Ig, is currently used in clinical transplantation to prevent allograft rejection and minimize the toxic side effects of calcineurin inhibitors. Despite reduced side effects and improved graft survival, belatacept-treated patients have higher rates of acute cellular rejection compared to CNI treatment. C) Limiting Trafficking of Alloreactive Memory T Cells pretransplant treatment with anti-LFA-1 mAbs inhibited early infiltration of endogenous donor-reactive memory CD8+ T cells into cardiac allografts, and significantly prolonged allograft survival (135). These findings suggest that a short course of integrin blockade may be instrumental in controlling T cell memory while avoiding side effects of long-term treatments.
Origin of allograft reactive memory T cells
They arise by identification of peptides from commensal bacteria or antigens presented by self-MHC, similar to complexes formed by allogeneic MHC molecules bound to other peptides leading to heterologous immunity .
Transplant patients can be sensitized through previous transplants, pregnancies, and blood transfusions.
Alloreactive memory T cells risk was higher in patients with prolonged dialysis periods.
It was published that low serum levels of 25-OH-vitamin D independently in dialysis patients correlates with the frequency of alloreactive memory T cells. Memory T cell location
Central T cells expresses CCR7 and CD62L, whereas and T cell effector memory T cells (Tem) express CCR7−CD62L
Trm cells has a defensive role against infections. It facilitates GVHD or allograft rejection thereby affecting graft survival.
CD4+CXCR5hi follicular helper (Tfh) cells within secondary lymphoid organs , are essential for B cell responses and antibody production. Low stimulation threshold and resistance to costimulatory blockage
memory T cells can respond to lower antigen doses with limited costimulation,leading to graft rejection. Role in allograft rejection
CD4 T h cells as well as its role in rejection it activates CD 8 T h cells. Memory CD4+ T cells evoke DSA by producing gamma interferon (IFNγ) secretion .
Increasing graft cold ischemia storage time enable memory CD8+ T cells rejection of a cardiac allograft despite costimulatory blockade with CTLA4-Ig.
Although memory T cells have negative drawbacks in the transplantation, they have regulatory capacity and suppress deleterious pro-inflammatory immune responses.
Shedding light that lymphoablative approaches targeting memory T cells can affect allograft tolerance in some transplants. Lymphoablation
Induction therapy uses Antibody-mediated lymphocyte depletion , specifically with highly sensitized recepients.
In rodents, after induction therapy with ATG prexisting memory T cells rapidly reoccur .The CD8+ T cells depletion is more efficient than memory CD4+ T cell depletion.
Alefacept targets alloreactive effector/memory T cells in solid organ and bone marrow transplantation . It synergizes with CTLA4-Ig by targeting costimulatory blockade-resistant CD8+CD2hiCD28− effector/ memory T cells. Costimulatory Blockade
Belatacept, a second generation of CTLA4-Ig, used to prevent allograft rejection and has lesser side effects than calcineurin inhibitors on the other side incidence of cellular rejection is higher than with CNI. Limiting Trafficking of Alloreactive Memory T Cells
a short course of integrin blockade can control T cell memory and at the same time avoiding side effects of long-term treatments.
Role of Memory T Cells in Allograft Rejection and Tolerance
In the absence of prior exposure to alloan- tigens, 1–10% of these memory T cells can react to allogeneic major histocompatibility complex (MHC) molecules.
these cells called endogenous or natural alloreac- tive memory T cells recognize intact allogeneic MHC molecules through the direct allorecognition pathway .
these memory cells are generated through the recognition of peptides from commensal bacteria or environmental antigens presented by self-MHC, which can mimic complexes formed by allogeneic MHC molecules bound to other peptides.
Such antigen mimicry, named “heterologous immunity.
Ex – following an EBV infection, HLA-B8+ individuals can become sensitized to the allo-MHC molecule HLA-B4402 through antigen mimicry resulting from the presentation of some viral or parasitic peptides.
prolonged exposure to dialysis increases the risk of developing alloreactive memory T cells.
low serum levels of 25-OH-vitamin D in dialysis patients correlates with the frequency of alloreactive memory T cells independent of age, gender, previous transplants, or time on dialysis .
Location of Memory T Cells-
Central memory T cells
effector memory T cells
memory T cells in secondary lymphoid and non-lymphoid peripheral tissues are spared by antibody-mediated lymphoablation Trm cells may be harder to control compared to circulating memory T cells.
memory T cells to respond to lower antigen doses with limited costimulation, i.e., to antigen presented by non-professional antigen-presenting cells .
memory CD4+ T cells not only become effector cells upon reactivation, but also provide help for the robust activation of donor-reactive effector CD8+ T cells (40). These effector CD8+ T cells then are the main driving force behind allograft rejection facilitated by memory CD4+ T cells.
Memory T cells under certain circumstances demonstrate regulatory capacity and suppress deleterious pro-inflammatory immune responses.
Recent developments –
Lymphoablation
Using ATG
Alefacept, a fusion protein combining extracellular domain of LFA-3 with constant regions of human IgG1.
Co stimulatory blockade
Belatacept, a second generation of CTLA4-Ig.
terminally differentiated memory CD4+ and CD8+ T cells in humans (Temra) lose CD28 expression and become insensitive to the lack of CD28/B7 costimulation.
Limiting Trafficking of Alloreactive Memory T Cells
Using LFA-1 and VLA-4 blocking abs.
Memory T cells has low activation threshold are characterized by their low activation threshold, strong effector function and resistance to conventional immunosuppressants. 1–10% of memory T cells generated through the recognition of peptides from commensal bacteria or environmental antigens can react to allogeneic major histocompatibility complex (MHC) molecules. Previous history of transplants, pregnancies, and blood transfusions confer alloantigen sensitization. Besides, homeostatic proliferation in a lymphopenic environment produce memory T cells that potentially impair tolerance induction to allografts. On the other hand, dialysis vintage and low serum levels of 25-OH-vitamin D in ESRD recipients correlates with the frequency of alloreactive memory T cells. Memory T cells divided into two major subsets with Central memory T cells express lymphoid homing markers CCR7 and CD62L, whereas effector memory T cells are CCR7−CD62L promote migration into peripheral cells. These T cell receptors and costimulatory signalling cascades enable memory T cells to respond to lower antigen threshold. Upon reactivation, memory CD4+ T cells become effector cells and activated the donor-reactive effector CD8+ T cells which contribute to the allograft rejection. Besides, the present of memory T cells pre transplantation has been associated with an increased risk for acute rejection among renal transplant recipients.
To overcome the consequence of alloreactive memory T cell in transplant rejection, the direct lymphoablation provide promising result in renal transplantation. Limiting CD4+ T helper signals during lymphoablation control the memory T cell expansion. Alefacept synergizes with CTLA4-Ig targeting alloreactive effector and memory T cells. Belatacept which is a second generation CTLA4-Ig prevent allograft rejection improve graft survival and reduce the side effect of CNI.
Meanwhile, reagents blocking LFA-1 (leukocyte function-associated antigen-1, an αLβ2 integrin) and VLA-4 (very late antigen-4, an α4β1 integrin) shown the ability to provide prolong allograft survival by prevent the early infiltration of endogenous donor-reactive memory CD8+ T cell into allograft.
In conclusion, memory T cells accelerate the risk of allograft rejection which compromise transplant tolerance. It is of great challenge for the diagnosis of T cell allosensitization among transplant recipients due to high heterogenicity of memory T cells. Besides, memory T cell shown variation of susceptibility to immunosuppressants. Further larger trial is needed for the development of novel approaches to control memory T cells and improve renal transplants survival.
Origin of alloreactive memory T cells:
Memory T cells are around 5-10% of all T cells. the source of these memory cells is an infection, exposure to environmental antigens, and in patients with ESRD some factors like exposure to dialysis & the low level of 25 OH-vitamin D.
Location of memory T cells:
Why memory cells are important in renal transplantation
Not well-evaluated pre-transplant (crossmatch is only evaluating preformed antibodies)
lower activation threshold
persist for a long time when compared to naive cells
resistant to co-stimulation signals
resistant to regulatory T cells
not suppressed by conventional maintenance immunosuppressive drugs and also resistant to induction therapy
Role in allograft rejection:
once memory CD4+ T cells get activated, they transform into effector t-cells rapidly & also activate CD8+ T cells and cause direct graft destruction. it also differentiates into THF and causes b-cell stimulation, DSA formation, and ABMR.
Influence of memory T cells on allograft tolerance:
Under certain circumstances, memory T cells show a regulatory effect and suppress the immune response and there is concern regarding depleting lymphocyte induction may interfere with graft tolerance.
Recent developments in targeting alloreactive T cell memory
Summary
The memory T cells have 3 major identifying characteristics. These include the following :
Alloreactive T cells can develop affinity by prior exposure to allogenic MHC molecules or by microbial infection. This poses a high risk for rejection.
They can originate from microbes or antigens presented by self MHC molecules. These can mimic allogenic MHC molecules. Thus, infection, blood transfusion, pregnancy, and previous transplants can all be a risk factor for rejection. Long dialysis period can be an additional risk factor for increased number of alloreactive memory T cells. This could be because of low serum 25-OH vitamin D.
There are 2 types of memory T cells :
Heterologous immunity may or may not translate into worse transplant outcome. Memory T cells may be alloreactive and lead to graft rejection, but they have 1 major advantage :
Alloreactive memory T cell targeting therapy includes the following options :
Diagnosing memory T cells will need tests that analyse cytokine production, follicular helper T cells. Peripheral blood samples need to be taken to identify memory T cells.
Summary of Role of Memory T Cells in Allograft Rejection and ToleranceABMR is amajor cause of graft dysfunction ,the B cell is corner stone of interaction of immunological process(ABMR).
Route of Ag presention to Bcellsor B cells activating
1-intact soulable Ag through B cell receptor(BCR) enages intact Ag displayed on FDCs, Bcell or macrophage.
2-entering L.N through multiple routes depend on Ag size,presence of Ag Ab and complement,in addition to migratory DCs.
3-enteringwhite pulp spleen .the B cells is presenting the Ag to cells
small soulable protein< 14kd it direct activate B cells through FRC conduct (in L.N or spleen).
the DSA and poly reactive antibodies bind to soulable Antigens and activate complement receptor3(CR3,CD11b,CD18) so opsonized Antigens by B cells in follicles through complement receptor CD21(CR2) and CD35(CR1) or FCRY11B receptors.
Ags bound to macrophages and DCs in L.N these DCs and macrophages together with CD8 DCs,M2 metallephill macrophage and M2macrophage capture Ag viaSIGLECI,SIGNRI,TIR andc-type lectin and finally the Ag activate complement and they opsanized Ag delivers by CRI on FDS.
extracellular vesicular exosomes realease by allograft are capture by SIGN-RI M2 macrophage.FA180 then drain into L.N or spleen where presented DCs donor MHC delivered by exosomees to recipients DCs and stimulate CD8 Tcell via direct way.
glyco protien with salcilic acid capture by sialodhesion (CD 169) , the macrophage deliver exosome donor MHC to FDCS with Bcell zone.
early Bcells activate by non-antigen specific Bcells or specific antigen (BCR-bound Ag)and interact with antigen specific Tcell receptor on CD4 Tcell and recognize MHC of recipient so Tcell have indirect specificity for MHC molecule expressed by recipient Bcell so activate or differentiate recipient Bcell into PCS producing DSA. The activation of the Tcall require DCS that acquired antigen from allograft and migrate to lymphnode when DCS arrive in the tissue.
Large antigen such as capture particular vaccine antigen, pathogen and allograft-drived exosome and membrane fragment so DCS process and present capture antigen to Tcell inducing Tcell response more rapidly then independently migration DCS.
TCR signaling strength are unclear and their differentiation into Tfh also require specific signals drived from the TCR .
Bcell at the T/B interfere result in producing PCS,memory Bcells as Bcells.
the pre GC response generate PCs that lower affinity than post -GCPCs so importance of the pre GC response to DSA production following solid organ transplant and contribution of this response to AMR has not been delineated.
Germinal center response
xtra follicular Bcells receive stimulation for follicularTfh cells.
ethey down regulate EB12.EB12 which realse Tcells. from out er follicule
in the absence of Tcell survival signals .Bcell undergo apoptosid in the light zone.
Belatacept inhibit Bcell and Tfh interaction so can control humeral response but still under under study.
Germinal centers responses to
consist of light and dark zone
the light zone contain FDCs and Tf.
dark zone is devoid FDCs.
Light zone B cells express CD86 and CD 38.
Bcells selected proliferate develop BCR specificity
some observation lead the author to suggest that TG-B production may be the mechanism by which Tfr inhibit B cell.
Generation of memory Bcells and pcs..
plasma cell function is control of infection ,produce memory cel and protection against reinfection.
memory Bcells has 2 phases
1-early pre GC memory Bcells ,with lower affinity for IgM .
2- late phase post GC memoray Bcell with higher affinity and expressing IgM or IgG.
memory B cells generated in the pre GC and early GC peroid so pc later long lived
affinity and kinetics of memory B cell versus PC differentiation suggest that treatment of AMR and reduction of circulatory DSA may not prevent memory donor-specific B cell generation.
recent meeting 2017 by sensitization in transplantation Assessment of risk working group they mention that non existence of DSA does not equate to an absence of sensitization of memory B cells.
other explanation for humeral sensitization without DSA in Transplant recipeint include absorption of DSA by the allograft..
absence of clinical test of donor specificity memory B cells so STAR recommended the only patient without DSA and also without HLA sensitizing events such as pregnancy,blood transfusion and previous transplant ,implement should be consider immunological lower lower risk for alloimmune memory.
Recall Bcell Respones
memory B cells differentiate into PCS by 2 ways
1-faster and high titre of antibody response,
2-higher affinity and class -switch PCs generate from GC B cells
IgG memory B cell predominate are IgM memory B cell in response of circulating antibodies.
factors affect rating of memory B cell up the Ag is depend on :
input , and type of memory B cell was generated and condition of Ag.
Conclusion
de novo DSA is major cause of allo graft loss.
this review summarized the cellular process that generate an antibody response but not non Ab producing role of B cells.
insights into mechanism lead to Ab production and humeral memory from study of model Ags and how these process are altered by feature of organ transplant require further investigation.
failure of successful transplant influence by factors impact
1-on the cellular response that generate PCs .
2-quality of producing DSA.
3-the quality of memory donor specific B cells.
anew way to control DSA production while preserving protective immunity is a result of difference between immune response to moderate Ags pathogens and transplant antigens.
when initial Abs is producing these Abs bind to same epitopes driving thier production either selection of B cells with higher affinity than circulating Abs or in selection of B cell with specificity for new epitopes
response subset of CD4T cell that express the regulators T(treg) cell master regulator FOXP3 showing many phenotype characteristics of Tfh cells has .
Memory Tcells
Benefits : rapid , strong effect on re-exposure to infections also in vaccinations and tumors .
Disadvantages : allograft rejection resistance to traditional immunosupression
*Origins of Alloreactive Memory T Cells :
•previous transplants, pregnancies, and blood transfusions.
•homeostatic proliferation in a lymphopenic environment
•end stage organ disease or treatment common in transplant candidates e.g vit D Defeciency
* memory T cells to respond to lower antigen doses with limited costimulation
this process is essential for host defense, it renders alloreactive memory T cells more dangerous in transplant
gamma interferon (IFNγ) secretion by memory helper T cells is required for de novo DSA generation
no indication that the presence of “heterologous immunity” in transplant recipients correlates with worse graft outcomes
ReCenT DeveLOPMenTS in TARgeTing ALLOReACTive T CeLL MeMORY
•Lymphoablation : ATG lymphoablation
•Costimulatory Blockade : second generation of CTLA4-Ig Belatacept
preventing memory T cell entrance into graft tissue should improve transplant outcome,the attempts to neutralize chemokines or chemokine receptors such as CCR5 or CXCR3 did not live up to the initial expectations
· Characteristics of memory cells include:
1-Low activation threshold
2-Potent effect or functions
3-Resistant to conventional immunosuppression
4-Resistant to co-stimulation blockade
They have an important role in alloreactive rejection.
Alloreactive memory T cells can be generated through heterologous immunity in mice previous transplants, pregnancy or blood transfusions are known route of alloimmune sensitization in human and could be developed by long exposure to dialysis low serum 25(OH)Vit. D is correlated with their frequency.
· Memory T cell subsets:
1-central memory T cell (T cm): express CCR7 and CD621
2-effecror memory T cell(Tem): CCR7 CD promote migration
3- Terminally differentiated effector memory T cell (Temra): CD45RA+ but CCR7- CD621- CD28 –
4-Tissue resident memory T cells (T rm): express CD69 αEβ7 integrin CD103.
They have an important role in protection against infections but facilate GVHD or rejection (related to donor and recipients, respectively).
5-T follicular helper (T fh): CD4+ CXR5 high3 important for B cell responses.
Memory T cell when reencounter to low antigen doses even with limited costimulation pathways activation such as CD28/CD80/CD86 and CD40 CD154, can activate rapidly.
This property is troublesome in transplantation.
Memory CD4+ T cell are resistant to common immunosuppression and result in DSA formation and ABMR. Therapeutic option is IFNγ inhibitors, neutralizing B cell activating factor and proliferation –inducing ligand.
Donor –reactive memory CD8+ T cell upregulates adhesion molecules and chemokines and result in leukocyte infiltration in to the graft.
In graft, memory CD8+ T cell proliferate and express ICOS and secrete IFNγ and result in in graft rejection.
Endogenous memory T cell can prevent transplant tolerance and is correlated with poor TX outcome. But under certain circumstances they represent regulatory capacity. For example, after treatment with CTLA-4 Ig and anti-CD159 mAbs in lung TX, Tcm CD8+are essential.
· Treatment for alloreactive T cell memory:
· 1-lymphoablation:
Lymphocyte depletion Anti-bodies in form of induction therapy is commonly used to prevent AMR.
But these drugs are not effective in depletion of memory CD4+ T cell.
Depletion of residual cd4+ T cell impairs the recovery of memory CD8+ T cells after ATG usage.
A synergic effect between ATG and blockage of costimulation.
Alefacept is a fusion protein depletes CD45 RO+ effector / memory T cell and can control effector /memory T cell in TX and have synergist effect with CTLA4-Ig by targeting CD8+ CD2 hi CD28 – T cells is seen.
Recently regulation of cell metabolic pathways is another strategy to target memory T cells.
· 2-Costimulatory blockage:
Memory T cell lose CD28 expression. So, they become resistant to the lack of CD28/B7 costimulation (belatacept). CD57+ CD4+ T cell subsets are belatacept- resistant, too.
Whereas tacrolimus has some effect on this subset.
Limiting trafficking of alloreative memory T cell by blocking chemokines or their receptors is another option.
For example, pre transplant treatment with anti-LFA-1 m Abs can inhibit memory CD8+ T cell.
Conclusion: Alloreactive memory T cell promotes rejection and prevent tolerance.
But use of these information in clinical TX is limited.
Memory T cells develop either due to exposure to peptides from commensal bacteria or environmental antigens ;heterologous immunity or antigen mimicry, exposure to alloantigen eg blood transfusion, pregnancy, prior transplant or through homeostatic proliferation in a set up of lymphopenia.. They reside in and circulate in peripheral non-lymphoid tissue. They are subdivided into different groups :Tcm (central, CCR7+CD62L+), Tem (effector, CD44+CD28+), Temra (effector with CD45RA+), Trm (tissue resident, CD103+CD69+) & Tfh (follicular helper cells, CXCR5+). Memory T cells have significant criteria eg low activation threshold with good effector functions and they resistance to conventional immunosuppression and co stimulation blockade. Memory Helper T cells release interferon gamma leading to DSA formation. Memory CD4+ T cells, with reactivation, leads to effector cells formation and activate donor reactive effector CD8+ T cells resulting in acute rejection. Circulating memory CD8+ T cells, during contact with donor endothelium, result in increased adhesion molecules and chemokines causing infiltration of recipient leukocytes into the graft, their proliferation and interferon release leading to rejection. Memory T cell correlates with poor graft outcomes and is an important obstacle for tolerance. Other obstacles in clinically utilizing data of memory T cells are there regarding diagnostics , the sampling utilizing peripheral blood and non availability of data regarding the tissue resident memory T cells. In addition,, discrepancy in results of animal and human models and susceptibility of the memory T cells to immunosuppression is related to their origin.
Memory T cells exhibit surface phenotypic markers that distinguish them from naïve counterparts and also reflect their enhanced functional and migration properties. The enhanced expression of activation markers such as CD45RO, and adhesion molecules such as LFA-1 (CD11a) and CD44, on memory vs. naïve T cells are thought to promote efficient interactions with APC and extravasation into inflammatory sites .More recently, expression of the lymph node homing receptors CCR7 and CD62L have been found to vary among memory T cells . In general, expression of CCR7 and CD62L is high in naive cells, connoting their preferred trafficking to lymphoid tissue , whereas memory CD4 and CD8 T cells comprise heterogeneous populations of CCR7+/CD62Lhi and CCR7−/CD62Llo subsets. These phenotypic distinctions have been shown to delineate functional subsets of memory T cells, designated central memory (CD62Lhi/CCR7+) and effector memory (CD62Llo/CCR7−) . The CD62Lhi/CCR7+ memory CD4 T-cell subset from human peripheral blood was found to lack effector function and produce primarily IL-2 , although virus-specific human and mouse central memory CD4 and CD8 T cells were found to exhibit ample effector function . In vivo, central memory CD8 T cells yielded greater protective immunity to LCMV infection in mice compared with the effector-memory subset . Therefore, the effector capacity of memory subsets that differ in homing receptor expression may likely differ according to the antigenic system. It will be important in future studies to establish the respective roles of central and effector memory T cells in allograft rejection.
These variations in homing receptor expression on memory T cells reflect their broad tissue distribution in both lymphoid and nonlymphoid sites including lung, liver, kidney, intestine, and also the brain .It has been shown that memory CD8 T cells in peripheral tissues, unlike memory CD8 T cells in lymphoid tissues, can spontaneously lyse target cells upon antigen reencounter, without the need for clonal expansion and differentiation . Thus, memory T cells have an ‘anatomic advantage’ over naive cells in that they are poised to exhibit immediate function at the site of antigen reencounter, bypassing the need for antigen presentation in the local lymph node. In graft rejection, Lakkis and colleagues have directly demonstrated the relevance of this memory cell advantage by showing that allospecific memory T cells, but not naive T cells, can efficiently reject cardiac allografts in the absence of secondary lymphoid tissue. Thus, memory T cells may have the potential for mediating early rejection responses owing to their rapid trafficking.
Activation requirements and functionOn per cell basis, antigen-specific memory T cells have less stringent activation requirements and exhibit enhanced activation compared with antigen-specific naive T cells. These properties have been demonstrated using T cells isolated from TCR-transgenic mice (TCR-tg) in which a majority of CD4 or CD8 T cells express a defined TCR specific for a given peptide antigen/MHC complex. Using TCR-tg systems, it was found that CD8 memory T cells specific for alloantigen exhibit rapid effector function, faster proliferation, increased responses to low antigen doses and direct cytolytic activity compared with allospecific naive CD8 T cells . Similar analyses have not been accomplished using alloantigen-specific TCR-transgenic CD4 T cells, although TCR-tg CD4 T cells specific for nominal antigenic peptides likewise exhibit immediate effector responses at low antigen doses . Memory T cells therefore have a kinetic and dose–response advantage over naive T cells.
Memory T cells also have less stringent activation requirements and are more permissive to activation by different APCs , compared with naive counterparts. Naive T cells require CD28/B7-mediated costimulation (signal 2) provided by professional APCs such as dendritic cells; however, memory T cells can be fully activated in the absence of costimulation via the B7/CD28 or CD40/CD154 pathways, and by many nonprofessional APC types such as resting B cells and macrophages . Moreover, Pober and colleagues have shown that memory, but not naive, allogeneic CD8 T cells can become activated, expand, and differentiate into cytotoxic T cells by coculture with endothelial cells . When taken together, it is clear that memory T cells, owing to their unique trafficking patterns, reduced activation requirements, and instantaneous recall may not only be the vanguard of T cells to arrive in an allograft, but are also capable of rapidly initiating endothelialitis and vascular rejection.
Effect of Memory T Cells on Allograft SurvivalThe critical role of T cells in ‘second set’ rejection has been established by the demonstration that accelerated rejection of secondary allografts can occur in alloantigen-primed animal models in the complete absence of B cells and circulating antibody . In patients, the presence of alloreactive memory T cells has been more difficult to assess. Sensitized transplant recipients are typically identified based on the presence of circulating anti-HLA antibodies, and it is well known that highly sensitized individuals have increased rejection episodes and inferior graft survival compared with unsensitized recipients . Because T-cell activation is necessary to provide ‘help’ as a prerequisite for B-cell activation and subsequent antibody production, it is likely that these sensitized individuals possess allospecific memory T cells. Heeger and colleagues have directly demonstrated the presence of primed allospecific memory T cells in transplant recipients using a sensitive ELISPOT assay based on cellular quantitation of effector cytokine producers . Using this assay, they provide evidence, in a small cohort of patients, that the pretransplant frequency of primed, donor-reactive cells in recipients of living donor kidneys correlates with the post-transplant risk of developing acute rejection episodes. These studies suggest that the presence of alloreactive memory T cells may impact survival of an allograft.
A major question that emerges when considering memory T cells in the transplant recipient is whether memory T cells are equally susceptible to current immunosuppression regimens. While little is known concerning the effects of immunosuppression on immune memory, the distinct signaling, cytokine, and survival requirements of memory vs. naive T cells suggest that memory T cells and/or memory subsets may be differentially affected by specific immunosuppressants. For example, both mouse and human memory T cells exhibit distinct TCR-mediated signaling compared with naive T cells , potentially affecting their susceptibility to cyclosporine and tacrolimus, which both target the TCR-coupled signaling pathway leading to IL-2 gene transcription. In addition, priming for memory recall responses has been shown to occur in vitro in the presence of cyclosporine , raising the possibility that alloreactive memory T cells could be generated in immunosuppressed individuals.
Other immunosuppressants that target cytokine responses may also differentially affect naive vs. memory T cells. While IL-2 is involved in the clonal expansion of naive T cells, memory CD8 T cells can divide independently of IL-2 and elicit effector function in the absence of division . Therefore, IL-2-receptor blocking drugs that interfere with IL-2 responses of T cells may not inhibit the potent functions and expansion of memory T cells. However, other cytokines, such as IL-7 and IL-15, have been found to affect both memory CD4 and CD8 generation, homeostatic proliferation and/or survival . For memory CD8 T cells, IL-15 is required for their homeostatic proliferation in vivo, but appears dispensable for antigen-driven proliferation . While memory CD4 T cells do not require IL-15 for homeostasis, IL-7 appears important for memory CD4 T-cell generation and survival . These results suggest that interfering with responses to IL-7 and IL-15 may affect the generation, survival and/or homeostatic turnover of memory T cells in vivo.
Resistance of Memory T Cells to Tolerance InductionInduction of donor-specific immunologic tolerance remains the ultimate goal in transplantation. Over the past several decades, a great deal has been learned about the mechanisms regulating primary immune responses, including utilization of adhesion molecules, chemokines, costimulatory pathways, and signaling pathways. Based on this knowledge, numerous strategies have been developed in small animal models, which have resulted in significantly prolonged allograft survival or even tolerance induction . Costimulation blockade of the CD154/CD40 pathway in the presence of donor-specific transfusion (DST) has been remarkably successful in promoting permanent survival of heart and islet allografts. However, this same strategy is wholly ineffective if the recipient has been previously primed with donor-specific antigen . Likewise, infection with Leischmania major or LCMV has been shown to generate primed T cells specific for certain mouse haplotypes, and this cross-reactive, allospecific memory is also refractory to tolerance induction strategies using costimulation blockade. Similarly, a regimen of combined CD28/CD40L blockade in combination with donor bone marrow and nonmyelosuppressive conditioning results in donor-specific tolerance of C57/BL6 hosts to BALB/c skin grafts, which does not occur if the recipient has been previously infected with LCMV. These results indicate that alloreactive memory T cells can mount effective rejection responses in the absence of costimulation, consistent with in vitro results . It has been suggested that failure of costimulation-based tolerance induction strategies in large animals may be owing to the increased proportion of memory T cells in these hosts compared with young rodents housed in pathogen-free conditions ; however, this idea has not yet been subject to experimental testing.
Additional evidence suggesting the refractory nature of memory T cells to tolerance induction strategies derives from studies on autoimmune type I diabetes. Transplantation of syngeneic islets into autoimmune diabetic NOD mice results in rapid destruction of islet grafts, characteristic of a secondary response, and referred to as recurrent autoimmunity. Numerous strategies shown to prevent primary disease in NOD mice are ineffective against recurrent autoimmunity in islet T-cell transplantation, where reactivation of memory T cells is likely to occur.
Despite their insensitivity to costimulation blockade in vivo, memory T cells are not inherently refractory to tolerance induction. For example, in vivo tolerization of antigen-specific mouse memory CD4 and CD8 T cells has been shown to occur following administration of high doses of intravenous soluble peptide antigen or low-avidity agonist-altered peptide ligands . Crosspresentation of peptide antigens by resting APC can also induce tolerance of memory T cells ( In addition, we have shown that memory T cells are not terminally differentiated, but rather can display functional flexibility and plasticity and recently, it has been shown that memory CD8 T-cell responses to allografts can be inhibited by CD4+ CD25+ regulatory T cells in vivo . When taken together, these results suggest that memory T cells are amenable to functional modulation. Further studies elucidating the mechanisms of memory T-cell functional plasticity and modulation will be critical in the rational design of strategies to induce tolerance of allospecific memory T cells.
Potential roles for memory T cells in transplant rejectionThe enhanced functional properties and diversity of memory T cells discussed above suggest that memory T cells may potentially participate in early and late graft rejection by a number of different mechanisms,. Because effector-memory T cells can recirculate in peripheral tissues, memory T cells may be rapidly recruited and initiate early responses directly at the graft site. These effector-memory T cells could immediately produce effector cytokines in situ that recruit additional immune cells for early graft tissue damage .
memeory T cell are characterized by
· low activation threshold
· robust effector function
· resistant to conventional immunosuppression and costimulation blockade .
T cells reside in and circulate through non lymphoid tissue .
Alloreactive memory T cells are subdivided into different categories based on their origin, phenotypes and function.
Sensitized individual display high alloreactive memort Tcells.
Allorective memeory T cells has major role in graft rejection and prevention of graft tolerance.
Immune response against antigens are beneficial during infection ,vaccinations, and tumor surveillance . Conversely, allorective T cell immune response against alloantigens in graft is detrimental.
Despite the potential harmfull effect of memory T cell ,its impact is neglected while choosing treatment regimens.
Memory Tcells comprises about 5-10% of all T cells .
heterologous immunity :- it is situation in which the memory cells is produced by recognition of peptide from bacteria or environmental antigens presented by self-MHC, which can mimic complexes formed by allogeneic MHC molecules bound to other peptides.
In humans, sensitization occur by previous transplants, pregnancies, and blood transfusions.
Prolonged dialysis increases the risk of developing alloreactive memory T Cells .
low serum levels of 25-OH-vitamin D in dialysis patients correlates with
the frequency of alloreactive memory T cells.
Memory T cells have been traditionally divided into two major subsets with largely overlapping functions but distinct trafficking patterns
· Central memory T cells (Tcm)
· effector memory T cells
In the process of memory T cell differentiation, the T cell
receptor and costimulatory signaling cascades are adjusted to ensure rapid activation of high magnitude upon antigen reencounter. This results in the ability of memory T cells to respond to lower antigen doses with limited costimulation, i.e., to antigen presented by non-professional antigen-presenting cells .While this process is essential for host defense, it renders alloreactive memory T cells more dangerous in transplant settings.
While de novo responses by naïve T cells can be efficient controlled by current immunosuppression, memory CD4+ T cells are resistant to these therapies and can provide help for the generation of DSA leading to alloantibody-mediated graft injury.
The potential therapeutic targets to control CD40-independent DSA generation by memory CD4+ T cells.
First, gamma interferon (IFNγ) secretion by memory helper T
cells is required for de novo DSA generation .
Second, CD40- independent helper functions of donor-reactive memory CD4+ T cells and heart allograft rejection were markedly inhibited by
neutralizing B cell activating factor and a proliferation-inducing ligand, cytokines critical for B cell survival, activation, and differentiation.
The presence of memory T cells has been often correlated with poor outcomes in clinical transplantation.
presence of memory T cells pretransplantation has been associated with an increased risk for acute rejection of kidney transplants . However, while EBV- and CMV-specific memory T cells displaying alloreactivity have been detected in human transplant recipients, so far there is no indication that the presence of “heterologous immunity” in transplant recipients correlates with worse graft outcomes.
Induction therapy is widely used in clinical transplantation to overcome the deleterious effects of preexisting donor-reactive immunity. Antibody-mediated lymphocyte depletion is most commonly used induction strategy, particularly in highly sensitized patients and in patients receiving marginal grafts. Although memory T cells are the primary targets of induction therapies, they are less susceptible to depletion than naïve T cells . The efficiency of memory CD4+ T cell depletion is generally lower than that of CD8+ T cells.
Belatacept, a second generation of CTLA4-Ig, is currently used to minimize the toxic side effects of calcineurin inhibitors. Despite reduced side effects and improved graft survival, belatacept-treated patients have higher rates of acute cellular rejection compared to CNI treatment . As memory T cells are more resistant to the effects of CTLA4-Ig in animal transplantation models, it is possible that presensitized T cells could account for some belatacept-resistant rejection episodes.
Not surprisingly, increased numbers of both CD4+ and CD8+ CD28- memory T cells are associated with a poor outcome in renal and lung transplant patients.
One study demonstrated that the sensitivity of memory T cells to immunosuppression is dependent on their origin.
CONCLUDING REMARKS.
other types of immunologic memory lymphocytes such as memory B cells, preexisting alloantibodies, and “innate memory” described for NK cells and macrophages can impact transplant outcomes, in this review, we focused exclusively on T cell memory.
It is now firmly established that alloreactive memory T cells accelerate allograft rejection and prevent transplant tolerance.
Difficulties
First, the diagnostics of T cell allosensitization in transplant candidates is problematic. Due to heterogeneity in phenotype and functions of memory T cells, complementary tests will be required including analyses of cytokine producing, cytotoxic, and follicular helper T cells.
Second, memory T cells in humans are sampled only in peripheral blood. So far, there is no information on pathogenicity of tissue-resident alloreactive memory T cells.
Third, memory T cell susceptibility to immunosuppression may depend on their origins. As immunological histories of individuals are difficult to trace, the situation may arise when patients with similar T cell memory profile require distinct treatment strategies.
Finally, despite rapidly accumulating data on alloreactive T cell memory, the discrepancies between animal models and transplantation in human patients
are profound.
BASIC BIOLOGY OF ALLOREACTIVE MEMORY T CELLS Origins of
Alloreactive Memory T Cells:
Alloreactive memory T cells recognize intact allogeneic MHC molecules through
Direct allorecognition pathway.
Indirectly as donor peptides–self-MHC complexes
It is probable that sensitized patients exhibiting high titers of all specific antibodies
display memory T cells recognizing alloantigens.
Memory T cells can also be generated through homeostatic proliferation in a
lymphopenic environment, including potentially alloreactive and pathogenic T cells.
The risk of developing alloreactive t cell increase also with:
Prolonged exposure to dialysis increases memory T cell.
In addition low serum levels of 25-OH-vitamin D in dialysis patients correlates with
the frequency of alloreactive memory T cell.
Location of Memory T Cells:
Memory T cells divided into two major subsets:
Central memory T cells (Tcm) express lymphoid homing markers CCR7 and
CD62L.
Effector memory T cells (Tem) are CCR7−CD62L.
Some T cells in peripheral tissues represent a distinct subset of tissue-resident
memory T cells, Trm cells express early activation marker CD69 and αEβ7 integrin
CD103 along with a number of tissue-specific chemokine receptors.
There is accumulating evidence that Trm cells play an important role in host
protection against infections AND transplant rejection.
Low Activation Threshold and Resistance to Conventional Costimulatory
Blockade:
In the process of memory T cell differentiation, the T cell receptor and
costimulatory signaling cascades are adjusted to ensure rapid activation of high
magnitude upon antigen reencounter This results in the ability of memory T cells to
respond to lower antigen doses with limited costimulation, i.e., to antigen presented
by non-professional antigen-presenting cells . While this process is essential for
host defense, it renders alloreactive memory T cells more dangerous in transplant
settings. Numerous studies in animal models have demonstrated that donor-
reactive memory T cells can induce allograft rejection despite interruption of
essential costimulatory pathways, CD28/CD80/CD86 and CD40/CD154
CONTRIBUTION OF MEMORY T CELLS TO ALLOGRAFT REJECTION AND
TOLERANCE:
Role in Allograft Rejection:
Memory CD4+ T cells not only become effector cells upon reactivation, but also
provide help for the activation of donor-reactive effector CD8+ T cells. These
effector CD8+ T cells then are the main driving force behind allograft rejection.
Memory CD4+ T cells are resistant to these therapies and can provide help for the
generation of DSA leading to AMR.
direct contact of circulating memory CD8+ T cells with donor endothelium
upregulates the expression of adhesion molecules and chemokines thus facilitating
infiltration of recipient leukocytes into the graft .
A proportion of endogenous memory CD8+ T cells react to donor MHC class I
molecules and can infiltrate allografts within hours after reperfusion. Once in the
graft parenchyma, these memory CD8+ T cells proliferate extensively, upregulate
the expression of ICOS, and secrete IFNγ in ICOS-dependent manner.
Influence of Memory T Cells on Allograft Tolerance:
T cells are generally viewed as pathogenic in the context of transplantation, under
certain circumstances, they demonstrate regulatory capacity and suppress
deleterious pro-inflammatory immune responses.
RECENT DEVELOPMENTS IN TARGETING ALLOREACTIVE T CELL MEMORY:
Lymphoablation:
Memory T cells are the primary targets of induction therapies, they are less
susceptible to depletion than naïve T cells.
T cells with an effector/memory phenotype are detectable after anti-CD52 mAb or
ATG induction and are associated with acute rejection episodes human transplant
recipients.
Limiting CD4+ T helper signals during lymphoablation increases the efficacy of
mATG in controlling memory T cell expansion and significantly extends heart
allograft survival in sensitized recipients These findings are consistent with
previous observations describing a synergistic effect between ATG lymphoablation
and costimulatory blockade.
Alefacept selectively depletes this subset and spares other T cell population.
Costimulatory Blockade:
Belatacept, a second generation of CTLA4-Ig, is currently used in clinical
transplantation to prevent allograft rejection. As memory T cells are more resistant
to the effects of CTLA4-Ig in animal transplantation models, it is possible that
presensitized T cells could account for some belatacept-resistant rejection
episode.
Limiting Trafficking of Alloreactive Memory T Cells:
Pretransplant treatment with anti-LFA-1 mAbs inhibited early infiltration of
endogenous donor-reactive memory CD8+ T cells into cardiac allografts, and
significantly prolonged allograft survival (135). These findings suggest that a short
course of integrin blockade may be instrumental in controlling T cell memory while
avoiding side effects of long-term treatments.
CONCLUDING REMARKS:
Alloreactive memory T cells accelerate allograft rejection and prevent transplant
tolerance.
Implementation of accumulated experimental knowledge in clinical transplantation
is impeded by several factors:
First, the diagnostics of T cell Allosensitization in transplant candidates is
problematic.
Second, memory T cells in humans are sampled only in peripheral blood. So far,
there is no information on pathogenicity of tissue-resident alloreactive memory T
cells.
Third, memory T cell susceptibility to immunosuppression may depend on their
origins.
Memory CD 4 T cell has a role in reactivation and also help donor-reactive effector CD8+ T cells which play a major role in allograft rejection so decreasing or depleting effector CD8+ T increase graft survival.
CD 4 T cell helps for the generation of DSA leading to alloantibody-mediated graft injury and unfortunately resistant to current immunosuppression.
Direct contact of circulating memory CD8+ T cells with donor endothelium upregulates the expression of adhesion molecules and chemokines thus facilitating infiltration of recipient leukocytes into the graft which increases risk of rejection and prolonged cold ischemia aggravate this cascade.
Allograft tolerance:The presence of memory T cells pre-transplantation are associated with an increased risk for acute rejection of kidney transplant but “heterologous immunity” in transplant recipients doesn’t correlates with worse graft outcomes ,so lymph ablative approaches targeting memory T cells may interfere with allograft acceptance of certain types of transplants.
Targeting allo-reactive memory cells:
Lymphoablation:
One of the most important strategy in sensitized recipients is induction therapy by ATG or alemtuzumab which is directed mainly to Memory T cells but its efficacy is less than naïve T cell.
Alefacept, a fusion protein which binds to CD2which is expressed on effector/memory T cells and depleting them so its used for targeting
costimulatory blockade-resistant CD8+CD2hiCD28 effector/memory T cells as coeffect for CTLA4-Ig .
Costimulatory Blockade:
Belatacept, a second generation of CTLA4-Ig, is currently used in clinical transplantation to prevent allograft rejection but terminally differentiated memory CD4+ and CD8+ T cells in humans (Temra) lose CD28 expression so become insensitive to CTLA4-Ig due to the lack of CD28/B7 co-stimulation.
Role of Memory T Cells in Allograft Rejection and Tolerance
BASIC BIOLOGY OF ALLOREACTIVE MEMORY T CELLS
T central memory cells (Tcm), express CCR7 chemokines which circulate through non lymphoid peripheral tissue and central lymphoid tissues with more proliferative activities
T effector memory cells (Tem ) express the chemokine receptor CXCR3 but lack CCR7, circulate more In nonlymphoid peripheral tissue and spleen , with immediate effect or function .
Tm cells have many advantages compared to their naïve T cells
More expression with longer half span wider migration pattern in lymphoid and nonlymphoid tissues need lower thresholds for reactivation with a strong recall immune response that resistant to treatment with CTLA4 Ig ( Belatocepts) as its recall immune response not dependent on costimulatory pathway , Tm cells reactivity mainly due to acquired alloreactive response to infection ,vaccination frequently due to cross reactivity with alloantigen . Second, alloreactive TM arise after exposure to alloantigen’s in blood transfusions, previous organ transplants, or pregnancy. Third, alloreactive TM arise during recovery from lymphopenia after induction with T cell depleting agents like ATG, alemtuzumab.
Tm cells can be activated can be activated outside secondary lymphoid organs—for example, in the graft itself.
prescence of pretransplant allogenic Tm cells assocaited with increase risk of acute rejection in presentized patinets
they are more resistant to depleting agents compared to naive cells
their effect on inducing tolererance depending on thier inhibitory expression ,data limited to animal studies,including trails trying to reduce the expression of different chemkinases at allogenic Tm activator receptors which may prevent graft rejction and imporve graft survival .
Several types of immunologic memory lymphocytes such as memory B cells, memory T cells ,preexisting alloantibodies, and “innate memory” described for NK cells and macrophages can impact transplant outcomes .Alloreactive memory T cells represent an essential element of the allograft rejection process and a major barrier to tolerance induction in clinical transplantation . they are characterized by their low activation threshold, robust effector functions, and resistance to conventional immunosuppression and costimulation blockade. therefore memory immune responses against donor antigens are detrimental in the context of transplantation and are commonly associated with poor graft outcome.
Origins of Alloreactive Memory T Cells : It is likely that these memory cells are generated through the 1)recognition of peptides from commensal bacteria or environmental antigens presented by self-MHC, which can mimic complexes formed by allogeneic MHC molecules bound to other peptides .
2) transplant patients can be sensitized from exposures to alloantigens such as previous transplants, pregnancies, and blood transfusions .
3) Memory T cells can also be generated through homeostatic proliferation in a lymphopenic environment, including potentially alloreactive and pathogenic T cells .
4) The accumulation of alloreactive memory T cells may be influenced by the end stage organ disease or treatment common in transplant candidates. For example, prolonged exposure to dialysis increases the risk of developing alloreactive memory T cells. In addition, Sawinski et al. reported that low serum levels of 25-OH-vitamin D in dialysis patients correlates with the frequency of alloreactive memory T cells independent of age, gender, previous transplants, or time on dialysis .
Location of Memory T Cells : Memory T cells have been traditionally divided into two major subsets with largely overlapping functions but distinct trafficking patterns. Central memory T cells (Tcm) express lymphoid homing markers CCR7 and CD62L, whereas effector memory T cells (Tem) are CCR7−CD62L− but instead express molecules that promote migration into peripheral tissues .
Recent studies demonstrated that some T cells in peripheral tissues do not circulate and represent a distinct subset of tissue-resident memory T cells (Trm) .There is accumulating evidence that Trm cells play an important role in host protection against infections. It is conceivable that Trm cells of both donor and recipient origins may influence transplant outcome by facilitating GVHD or allograft rejection, respectively .
RECENT DEVELOPMENTS IN TARGETING ALLOREACTIVE T CELL MEMORY
Lymphoablation Induction therapy is widely used in clinical transplantation to overcome the deleterious effects of preexisting donor-reactive immunity. Antibody-mediated lymphocyte depletion is most commonly used induction strategy, particularly in highly sensitized patients and in patients receiving marginal grafts Although memory T cells are the primary targets of induction therapies, they are less susceptible to depletion than naïve T cells ). T cells with an effector/memory phenotype are detectable after anti-CD52 mAb or ATG induction and are associated with acute rejection episodes. The efficiency of memory CD4+ T cell depletion is generally lower than that of CD8+ T cells Additional depletion of residual CD4+ T cells severely impairs the recovery of memory CD8+ T cells after ATG treatment .Limiting CD4+ T helper signals during lymphoablation increases the efficacy of mATG in controlling memory T cell expansion. These findings are consistent with previous observations describing a synergistic effect between ATG lymphoablation and costimulatory blockade). Alefacept, a fusion protein combining extracellular domain of LFA-3 with constant regions of human IgG1 LFA-3 is a ligand for CD2, a molecule that is predominantly detected on human T and NK cells. As CD2 expression is upregulated on CD45RO+ effector/memory T cells, alefacept selectively depletes this subset and spares other T cell populations Alefacept is currently being used in clinic for the treatment of severe psoriasis and is showing promise for targeting alloreactive effector/memory T cells in solid organ and bone marrow transplantation. Most importantly, pretransplant alefacept therapy synergizes with CTLA4-Ig presumably by targeting costimulatory blockade-resistant CD8+CD2hiCD28− effector/ memory T cells (91). In addition to direct lymphoablation, manipulating T cell survival and homeostasis by regulating cell metabolic pathways may be a promising therapeutic strategy in transplantation.
Costimulatory Blockade Belatacept, a second generation of CTLA4-Ig, is currently used in clinical transplantation to prevent allograft rejection and minimize the toxic side effects of calcineurin inhibitors. Despite reduced side effects and improved graft survival, belatacept-treated patients have higher rates of acute cellular rejection compared to CNI treatment . As memory T cells are more resistant to the effects of CTLA4-Ig in animal transplantation models, it is possible that presensitized T cells could account for some belatacept-resistant rejection episodes. Indeed, terminally differentiated memory CD4+ and CD8+ T cells in humans (Temra) lose CD28 expression and become insensitive to the lack of CD28/B7 costimulation). Not surprisingly, increased numbers of both CD4+ and CD8+ CD28− memory T cells are associated with a poor outcome in renal and lung transplant patients.
another major costimulatory pathway, CD40/CD154, encountered early difficulties because of thromboembolic effects of anti-CD154 (CD40L) blocking antibodies .To avoid cross-linking CD154 that is highly expressed on platelets, an alternative approach has been the generation of non-activating anti-CD40 antibodies. Several such reagents have been successfully tested in non-human primate recipients of renal and islet allografts
Limiting Trafficking of Alloreactive Memory T Cells : While preventing memory T cell entrance into graft tissue should improve transplant outcome, the attempts to neutralize chemokines or chemokine receptors such as CCR5 or CXCR3 did not live up to the initial expectations, most likely due to the redundancy of chemokine/receptor network
Memory T cells constitute around 5-10% of all T cells in mice. In the absence of prior exposure to antigens, only 1-10% can react to allogeneic MHC, the source of these memory cells is infection and exposure to environmental antigens ( heterologous immunity).
Memory T cells can also be generated through homeostatic proliferation in a lymphopenic environment and can impair tolerance to allografts.
The accumulation of these memory cells can be affected by the end-organ disease such as in patients with ESRD, prolonged exposure to dialysis & the low level of 25 OH-vitamin D in these patients lead to the development of memory cells.
Location of memory T cells:
Memory T cells are characterized by a low activation threshold and resistance to costimulatory blockade and this results in the ability of memory T cells to respond to lower antigen doses with limited co-stimulation.
Role in allograft rejection:
Upon activation of memory CD4+ T cells, they become effector cells & also provide help for the activation process of CD8+ T cells. These effector CD8+ T cells are the main driving force for rejection. Early direct contact of these cells with donor endothelium upregulates the expression of adhesion molecules and chemokines thus facilitating infiltration of the recipient leukocytes into the graft.
Memory CD4+ T cells are resistant to immunosuppressive medications and can provide help for DSA formation & ABMR.
Influence of memory T cells on allograft tolerance:
The presence of memory T cells Pre- transplantation has been associated with an increased risk of acute rejection, however, there is no indication that the presence of heterologous immunity( such as EBV, CMV-specific memory T cells) correlates with worse graft outcomes.
Under certain circumstances, memory T cells show a regulatory effect and suppress the pro-inflammatory immune response and there is concern about the lymphoablative approaches targeting memory T cells may interfere with allograft acceptance of certain types of transplants.
Recent developments in targeting alloreactive T cell memory
Lymphoablation: ATG, Alemtuzumab- less effective. Alefacept a recombinant dimeric fusion protein inhibits LFA3/ CD2 interaction and thus inhibits T cells activation, selectively depletes memory T cells, currently used for the treatment of psoriasis.
costimulatory blockade: Belatacept second generation of CTLA4-Ig is currently used to prevent rejection and minimize the toxic effect of CNI, but there is an increased incidence of cellular rejection compared to CNI as memory cells are more resistant to the effect of CTLA4-Ig and terminally differentiated memory CD4+, CD8+ T cells lose CD28 expression.
Limiting trafficking of alloreactive memory T cells: reagents blocking LFA-1 & VLA-4 have been demonstrated to prolong allograft survival in experiments.
alloreactive memory T cells represent an essential element of the allograft rejection process and a major barrier to tolerance induction in clinical transplantation
Origins of Alloreactive Memory T Cells
these memory cells are generated through the recognition of peptides from commensal bacteria or environmental antigens presented by self-MHC, which can mimic complexes formed by allogeneic MHC molecules bound to other peptides
For instance, following an EBV infection, HLA-B8+ individuals can become sensitized to the allo-MHC molecule HLA-B4402 through antigen mimicry resulting from the presentation of some viral or parasitic peptides
In humans, transplant patients can be sensitized from exposures to alloantigens such as previous transplants, pregnancies, and blood transfusions.
The accumulation of alloreactive memory T cells may be influenced by dialysis, low serum levels of 25-OH-vitamin D in dialysis patients correlates with the frequency of alloreactive memory T cells independent of age, gender, previous transplants, or time on dialysis
Location of Memory T Cells
Central memory T cells (Tcm) express lymphoid homing markers CCR7 and CD62L and
effector memory T cells (Tem) are CCR7−CD62L− express molecules that promote migration into peripheral tissues
memory T cells in secondary lymphoid and non-lymphoid peripheral tissues are spared by antibody-mediated lymphoablation
Low Activation Threshold and Resistance to Conventional Costimulatory Blockade
the T cell receptor and costimulatory signaling cascades are adjusted to ensure rapid activation of high magnitude upon antigen reencounter
This results in the ability of memory T cells to respond to lower antigen doses with limited costimulation, i.e., to antigen presented by non-professional antigen-presenting cells .
Role in Allograft Rejection
memory CD4+ T cells not only become effector cells upon reactivation, but also provide help for the robust activation of donor-reactive effector CD8+ T cells
These effector CD8+ T cells then are the main driving force behind allograft rejection facilitated by memory CD4+ T cells in heart-transplanted mice, and CD8+ T cell depletion or limiting their trafficking into the graft significantly extends allograft survival
While de novo responses by naïve T cells can be efficiently controlled by current immunosuppression, memory CD4+ T cells are resistant to these therapies and can provide help for the generation of DSA leading to alloantibody-mediated graft injury
influence of Memory T Cells on Allograft Tolerance
In laboratory rodents, endogenous memory T cells generated through heterologous immunity have little ability to prevent tolerance induction given that hematopoietic chimerism and/ or costimulation blockade regularly achieve tolerance of fully allogeneic transplants
In contrast, mice that have been sensitized to allogeneic MHC through transplantation or multiple viral infections become resistant to tolerance induction
Lymphoablation
memory T cells are the primary targets of induction therapies, they are less susceptible to depletion than naïve T cells
T cells with an effector/memory phenotype are detectable after anti-CD52 mAb or ATG induction and are associated with acute rejection episodes in non-human primates and human transplant recipients
The efficiency of memory CD4+ T cell depletion is generally lower than that of CD8+ T cells
Additional depletion of residual CD4+ T cells severely impairs the recovery of memory CD8+ T cells after ATG treatment
Costimulatory Blockade
Belatacept, a second generation of CTLA4-Ig, is currently used in clinical transplantation to prevent allograft rejection and minimize the toxic side effects of calcineurin inhibitors (97). Despite reduced side effects and improved graft survival, belatacept-treated patients have higher rates of acute cellular rejection compared to CNI treatment
As memory T cells are more resistant to the effects of CTLA4-Ig in animal transplantation models
Limiting Trafficking of Alloreactive Memory T Cells
pretransplant treatment with anti-LFA-1 mAbs inhibited early infiltration of endogenous donor-reactive memory CD8+ T cells into cardiac allografts, and significantly prolonged allograft survival
Conclusion
alloreactive memory T cells accelerate allograft rejection and prevent transplant tolerance.
diagnostics of T cell allosensitization in transplant candidates is problematic
memory T cells in humans are sampled only in peripheral blood. So far, there is no information on pathogenicity of tissue-resident alloreactive memory T cells
memory T cell susceptibility to immunosuppression may depend on their origins
# This article describes the different subsets of alloreactive memory T cells involved in transplant rejection, their generation, functional properties, mechanisms of action and discuss strategies developed to target deleterious allospecific memory T cells in experimental animal models and clinical settings.
* Memory T cells are characterized by:
low activation threshold
robust effector functions
resistance to conventional immunosuppression and costimulation blockade.
– Reside in and recirculate through peripheral non-lymphoid tissues. Alloreactive memory T cells are subdivided into different categories based on their origins, phenotypes, and functions.
– These memory cells are generated through the recognition of peptides from commensal bacteria or environmental antigens presented by self-MHC, which can mimic complexes formed by allogeneic MHC molecules bound to other peptides .
– This antige mimicry named “heterologous immunity,” is well documented in both humans and experimental animal models.
– After EBV infection, HLA-B8+ individuals can become sensitized to the allo-MHC molecule HLA-B4402 through antigen mimicry resulting from the presentation of some viral or parasitic peptides
– Alloreactive memory T cells essential element of the allograft rejection
– A major barrier to tolerance induction in clinical transplantation.
– Memory immune responses against
donor antigens are commonly associated with poor graft outcome.
– Despite well documented harmful effects of memory T cells in
transplantation the potential impact of such cells is mostly neglected while choosing treatment regimens.
– Transplant patients can be sensitized from exposures to alloantigens such as previous transplants, pregnancies, and blood transfusions.
– Sensitized patients exhibiting high titers of allospecific antibodies display memory T cells recognizing alloantigens indirectly as donor peptides–self-MHC complexes.
– Memory T cells can also be generated through homeostatic proliferation in a lymphopenic environment, including potentially alloreactive and pathogenic T cells .
– Such homeostatically expanded memory T cells can impair tolerance induction to allografts .
-Prolonged exposure to dialysis increases the risk of developing alloreactivememory T cells .
– Low serum levels of 25-OH-vitamin D in dialysis patients correlates with the frequency of alloreactive memory T cells independent of age, gender, previous transplants, or time on dialysis.
# Location of Memory T Cells
– Memory T cells have been traditionally divided into two
* Central memory T cells (Tcm)
express lymphoid homing markers CCR7 and CD62L.
* Effector memory T cells (Tem)
are CCR7−CD62L− but instead
express molecules that promote migration into peripheral tissues .
* Terminally differentiated effector memory T cells (Temra)
reexpress naive T cell surface marker CD45RA, while downr egulating expression of CCR7, CD62L, and CD28, and represent a terminal stage of effector differentiation .
– Resident memory T cells (Trm)
in peripheral tissues do not circulate and represent a distinct subset of tissue
express early activation marker CD69 and αEβ7 integrin CD103 along with
a number of tissue-specific chemokine receptors play an important role in host protection against infections. It may influence transplant outcome by facilitating GVHD or allograft rejection
* follicular helper cell (Tfh)
express CD4+CXCR5hi that reside in B cell follicles within secondary lymphoid organs and are essential for optimal B cell responses and antibody generation
Memory T cells in secondary lymphoid and non-lymphoid peripheral tissues are spared by antibody-mediated lymphoablation ,Trm cells may be harder to control compared to circulating memory T cells.
# Low Activation Threshold and Resistance to Conventional Costimulatory Blockade:
– Ability of memory T cells to respond to lower antigen doses with limited co- stimulation to antigen presented by non professional antigen presenting cells.
– While this process is essential for host defense, it renders alloreactive memory T cells more dangerous in transplant .
# CONTRIBUTION OF MEMORY T CELLS
TO ALLOGRAFT REJECTION AND
TOLERANCE
* Role in Allograft Rejection
– Memory CD4+T cells not only become effector cells upon reactivation, but
also provide help for the robust activation of donor-reactive effector CD8+ T cells -These effector CD8+ T cells then are
the main driving force behind allograft rejection facilitated bymemory CD4+ T cells .
– De novo responses by naïve T cells can be efficiently controlled by current immunosuppression.
– Memory CD4+T cells are resistant to these therapies and can provide help
for the generation of DSA leading to alloantibody-mediated graft injury.
– Gamma interferon (IFNγ) secretion by memory helper T cells is required for de novo DSA generation .
– Early direct contact of circulating memory CD8+ T cells with donor
endothelium upregulates the expression of adhesion molecules, chemokines and infiltration of recipient leukocytes into the graft .
# Influence of Memory T Cells on Allograft Tolerance:
– presence of memory Tcells pretransplantation has been
associated with an increased risk for acute rejection of kidney transplants . -EBV and CMV specific memory T cells displaying alloreactivity have been detected in human transplant recipients, there is no indication that the presence of “heterologous immunity” in transplant recipients correlates with
worse graft outcomes .
# RECENT DEVELOPMENTS IN TARGET
ALLOREACTIVE T CELL MEMORY
* Lymphoablation
– Antibody-mediated lymphocyte depletion is most commonly used induction strategy, particularly in highly sensitized patients and in patients receiving marginal grafts .
– Memory T cells are the primary targets of induction therapies, but they are less susceptible to depletion than naïve T cells , T cells with an effector/memory phenotype are detectable after anti-CD52 mAb or ATG induction and are associated with acute rejection episodes .
– The efficiency of memory CD4+ T cell depletion is generally lower than that of
CD8+ T cells .
– Alefacept, a fusion protein combining extracellular domain of LFA-3 with human IgG1 it depletes this subset and spares other showing promise for targeting alloreactive effector/memory T cells in solid organ and bone marrow transplantation .
– pretransplant alefacept therapy synergizes with CTLA4-Ig presumably by targeting costimulatory blockade-resistant CD8+CD2hiCD28− effector/memory T cells .
* Costimulatory Blockade
-Belatacept a second generation of CTLA4-Ig used in clinical transplantation to prevent allograft rejection and minimize the toxic side effects of CNI, it
treated patients have higher rates of acute cellular rejection compared to CNI treatment .
presensitized T cells could account for some belatacept-resistant rejection episodes.
– Terminally differentiated memory CD4+ and CD8+ T cells in humans lose CD28 expression and become insensitive to the lack of CD28/B7 costimulation.
– Increased numbers of both CD4+ and CD8+CD28− memory T cells are associated with a poor outcome in
renal and lung transplant
# CONCLUDING REMARKS
– Alloreactive memory T cells accelerate allograft rejection and prevent transplant tolerance.
– The diagnostics of T cell allosensitization in transplant candidates is problematic.
– Due to heterogeneity in phenotype and functions of memory T cells, complementary tests will be required.
The resulting information is hard to
use in clinical decision-making.
– No information on pathogenicity of tissue-resident alloreactive memory T cells.
– Finally, despite rapidly accumulating data on alloreactive T cell memory, the discrepancies between animal models and transplantation in human patients
are profound.
Role of Memory T Cells in Allograft Rejection and Tolerance
Memory T cells are a type of T lymphocytes generated either through exposure to peptides from commensal bacteria or environmental antigens (heterologous immunity or antigen mimicry), exposure through alloantigen (like blood transfusion, pregnancy, prior transplant etc) or through homeostatic proliferation in a lymphopenic environment. They stay in and circulate through peripheral non-lymphoid tissue. They can be subdivided into different groups including Tcm (central, CCR7+CD62L+), Tem (effector, CD44+CD28+), Temra (effector with CD45RA+), Trm (tissue resident, CD103+CD69+) and Tfh (follicular helper cells, CXCR5+). The memory T cells have low activation threshold with good effector functions and they are resistant to conventional immunosuppression and costimulation blockade. Memory Helper T cells release interferon gamma leading to DSA generation. Memory CD4+ T cells, on reactivation, give rise to effector cells and also activate donor reactive effector CD8+ T cells leading to acute rejection. Circulating memory CD8+ T cells, on contact with donor endothelium, lead to increased adhesion molecules and chemokines causing infiltration of recipient leukocytes into the graft, their proliferation and interferon release causing rejection. Memory T cell presence correlates with poor graft results and is a major obstacle to achieve tolerance. There are still many obstacles in utilizing the data on memory T cells clinically as the diagnostics are not easy, the sampling utilized is peripheral blood and no data exists regarding the tissue resident memory T cells. In addition, the results of animal and human models are not comparable and susceptibility of the memory T cells to immunosuppression depends on their origin.
Memory T cells increase the likelihood of graft rejection and decrease the likelihood of transplant tolerance.
The biology of alloreactive memory T cells at their most fundamental level
The following is the source:
The generation of memory cells following the detection of peptides from commensal bacteria or environmental antigens presented by the self-MHC is referred to as heterologous immunity. Patients undergoing transplantation who have been exposed to alloantigens, such as during pregnancy, blood transfusion, or a prior transplant, may develop sensitization.
T cells with the potential to be alloreactive and pathogenic may be created by homeostatic proliferation in a lymphopenic environment, among other things.
These cells may be created in individuals with end-stage organ illness; for example, dialysis increases the likelihood of the development of alloreactive memory T cells, and research found that low vitamin D levels in dialysis patients are associated with the frequency of alloreactive memory T cells.
Location:
Memory is the brain’s hippocampus T cells (Tcm) express lymphoid homing markers, which help them to find their way home.
Effector memory is a term used to describe the memory of an effector. T cells (Tem) produce chemicals that aid in the cell’s migration to peripheral organs.
Tissue-resident memory is a kind of memory that is found in tissues. Despite the fact that T cells are protective against infection, T cells in the recipient increase the likelihood of allograft rejection (its role in transplant is not well addressed)
Follicular helper cells (Tfh) are cells that reside in the B cell follicle of the secondary lymphoid organ and are essential for the development of the B cell response and the production of antibodies.
The low activation threshold and resistance to traditional costimulatory inhibition are two characteristics of this receptor.
They are more harmful in transplant because they react to modest antigen dosages with minimal costimulation, making them more deadly in transplant.
The role of the immune system in allograft rejection:
memory When CD4 T cells are reactivated, they become effector cells that aid in the activation of CD8 T cells as well as the creation of DSA memory cells. Immunosuppressive memory CD4 T cells are resistant to immunosuppressive memory. CD8 T cells stimulate the production of adhesion molecules, resulting in the infiltration of leucocytes into the graft.
Targeting alloreactive T cell memory has shown some recent advancements.
-Lymphoablation
It is common practice in clinical transplantation to provide induction treatment to patients in order to alleviate the negative effects of preexisting donor-reactive immunity. Antibody-mediated lymphocyte depletion is the most widely employed induction technique, especially in patients who are extremely sensitive to the procedure or who are getting marginal grafts.
-Blockade of the costimulatory system
Belatacept, a CTLA4-Ig of the second generation, is now being utilized in clinical transplantation to reduce allograft rejection while also reducing the harmful side effects of calcineurin inhibitors.
Despite fewer side effects and greater graft survival, individuals treated with belatacept had higher rates of acute cellular rejection when compared to those treated with CNI (contrary to CNI therapy).
· Memory immune cells paly critical role in protection from infection, benefit from vaccination and tumor surveillance. However, they are strong barriers against tolerance to transplanted cells.
· These memory cells are initially formed in both animal models and human, against certain infectious or bacterial antigens identified on MHC class II molecules of APC, then due to molecular mimicry between allogenic Ag in graft and the original Ag against which the memory cells are preformed, those memory cells represent a threat against the graft with rapid and intense immune response (heterologous immunity).
· In human, these memory cells also formed due to previous sensitization as (retransplantation, pregnancy or previous transfusion). Prolonged stay on dialysis and Vit D deficiency increase risk of formation of alloreactive T cells.
· In human, only memory T cells from sensitization represent risk of AR and worse graft outcome. However, those formed against EBV infection not affect graft outcome.
· The memory T cells either:
o Central present in lymphoid tissues.
o Circulating T memory.
· Unfortunately, those memory cells are activated by lower threshold or concentration of encountered Ag. Cytotoxic memory CD 8 cells are the dominator cells in inducing graft damage and loss, but it depends on signaling and activation from CD4 cells.
· In addition, T memory cells are not affected by lymph-depletion therapy than naiive T cell. They are less susceptible to induction with ATG or alemtuzumab ( monoclonal Ab against CD52 presented on both B and T cells).
· Belatcept (CTLA4 Ig), co-stimulation blockade between CD28 :B7, used to minimize exposure and toxicity of CNI. However, it is associated with higher rejection rate that can be attributed to its minimal effect on memory cells (less reactive to co-stimulation signals).
· Conflicting results from animal studies, which found that no difference in graft outcome according to presence of memory T cells or even they are required for graft tolerance and so memory T cell targeted therapy may decrease tolerance.
· Although, there is established evidence that memory T cells accelerate allograft rejection, many factors make the implementation of detected memory cells prior to transplantation and its reflection on immunosuppressive regimen individualization much more difficult as:
– The data from exclusive animal studies can not be applied to human.
– The effect of memory cells differ according to its origin (central or circulating).
– The lab analysis to detect them depend on identification of many cytokines (difficult and expensive).
– Just detection of memory cell in peripheral circulation (not tissue resident cells).
– Other co=existing factors as preformed DSA, cold ischemia time may contribute to AR and final graft outcome.
Q. I would like to ask about the appropriate method of summarizing an article, it should include all details or just the clinically applied points? for example, I do not read or take into consideration the types of expressed receptors on different types of cells?
-Memory T cells are characterized by their low activation threshold, robust effector functions,and resistance to immunosuppression and costimulation blockade. They reside in and recirculate through peripheral non-lymphoid tissues. -They represent an essential element of the allograft rejection process and a major barrier to tolerance induction in clinical transplantation.
– transplant patients can be sensitized from exposures to alloantigens such as previous transplants, pregnancies, and blood transfusions.
– sensitized patients exhibiting high titers of allospecific antibodies display memory T cells recognizing alloantigens indirectly as donor peptides–self-MHC
complexes.
-The accumulation of alloreactive memory T cells may be influenced by the end-stage organ disease or treatment common in transplant candidates.
-Prolonged exposure to dialysis increases the risk of developing alloreactive memory T Cells,and low serum levels of 25-OH-vitamin D in dialysis patients correlate with the frequency of alloreactive memory T cells independent of age, gender, previous transplants, or time on dialysis.
-Memory T cells have been traditionally divided into two: Central memory T cells (Tcm) and effector memory T cells (Tem).
-CD4+CXCR5hi follicular helper (Tfh) cells are memory T cells relevant to transplantation that reside in B cell follicles within secondary lymphoid organs and are essential for optimal B cell responses and antibody generation.
-Memory CD4+ T cells provide help for the robust activation of donor-reactive
effector CD8+ T cells which are the main driving force behind allograft rejection facilitated by memory CD4+ T cells in some experiments.
– Memory CD4+ T cells are resistant to immunosuppression and can provide help
for the generation of DSA leading to alloantibody-mediated graft injury.
-Gamma interferon (IFNγ) secretion by memory helper T cells is required for de novo DSA generation.
– Early direct contact of circulating memory CD8+ T cells with donor endothelium upregulates the expression of adhesion molecules and chemokines thus facilitating infiltration of recipient leukocytes into the graft.
– Memory CD8+ T cells inside the graft proliferate extensively, upregulate the expression of ICOS, and secrete IFNγ in an ICOS-dependent manner.
-Increasing graft cold ischemia storage time enhanced effector functions of
endogenous memory CD8+ T cells.
– The presence of memory T cells pretransplantation has been associated
with an increased risk for acute rejection of kidney transplants.
– Memory T cells may demonstrate regulatory capacity and suppress
deleterious pro-inflammatory immune responses.
-Antibody-mediated lymphocyte depletion is the most commonly used induction strategy, particularly in highly sensitized patients and in patients receiving marginal grafts.
-Memory T cells are the primary targets of induction therapies, they are less susceptible to depletion than naïve T cells.
-T cells with an effector/memory phenotype are detectable after anti-CD52 mAb or ATG induction and are associated with acute rejection episodes.
-The efficiency of memory CD4+ T cell depletion is generally lower than that of
CD8+ T cells . Depletion of residual CD4+ T cells severely impairs the recovery of memory CD8+ T cells after ATG treatment.
-Alefacept, a fusion protein combining the extracellular domain
of LFA-3 with constant regions of human IgG1, selectively depletes
CD45RO+ effector/memory T cells . Alefacept is used for the treatment of severe psoriasis and is showing promise for targeting alloreactive effector/memory T cells in solid organ and bone marrow transplantation.
-Belatacept, the second generation of CTLA4-Ig, is currently used in clinical transplantation to prevent allograft rejection and minimize the toxic side effects of calcineurin inhibitors but patients have higher rates of acute cellular
rejection compared to CNI treatment.
– Memory T cells are account for some belatacept-resistant rejection episodes.
-The sensitivity of memory T cells to immunosuppression is dependent on its origin.
-Preventing memory T cell entrance into graft tissue should improve transplant outcome, by the attempts to neutralize chemokines or chemokine receptors such as CCR5 or CXCR3.
-Reagents blocking LFA-1 (leukocyte function-associated antigen-1, an αLβ2 integrin) and VLA-4 (very late antigen-4, an α4β1 integrin) have been demonstrated to prolong allograft survival in experimental transplantation.
Conclusion:
– The diagnostics of T cell allosensitization in transplant candidates is problematic.
-Memory T cells in humans are only in peripheral blood. So far, there is
no information on pathogenicity of tissue-resident alloreactive
memory T cells.
-Memory T cell susceptibility to immunosuppression may depend on their origins.
this Article focus on characteristic features of reactivation and function of memory cell against graft and also to shed light on strategies for deleting and suppressing memory T cell to improve outcome of survival graft.
Basic Biology of alloreactive memory T cell: Experimental Study done on rodents shows in absence of exposure to previous antigen 10% of these memory T cell react to allogen MHC molecules in vitro these cell called endogenous or natural alloreactive memory T cell which recognise intact allogenic MHC molecule through direct alloreactive pathway. These cells may generated from previous exposure to bacteria & environmental Ag present in MHC molecule which mimic complexes formed by allogenic MHC molecule bound to other peptide. this immunity called heterologous immunity. this heterogeneous immunity develops in human & non human primates due to previous exposure to infective environment and pro inflammatory agents during development. E.g. exposure to EBV infection HLA B8 individuals become sensitised to allo MHC molecule HLA B 4402 and this due to adherence to viral and parasitic peptides. in laboratory rodent has direct sensitisation with skills allograft due to appearances donor reactive memory T cell. In human transplant patients can be sensitised to alloantigen due to previous exposure to transplant/ pregnancy and blood transfusion. until now high titer of allospecific antibody of memory T cell seen in sensitised patients.
accumulation of alloreactive memory cells are may be increased by end organ disease or due to immunosuppressive agents example long duration of dialysis are risk for increase alloreactive memory T cell. Also low vitamin D on dialysis patients are risk for formation of reactive memory cells.
Location of memory T cell:
divided into 1/ central memory T cell 2/ effector memory T cell
central memory T cell express lymphoid markers CCR7 & CD 621. effector memory T cell promote migration to peripheral tissue.
In human some memory T cell differentiated effector memory T cell express native T cell. this cell located in peripheral tissue and not circulating. Trm cell express early activation markers CD69 & a EB7 integrin CD 103 along with number of tissue specific chemkine receptor. Trm cell play important role in host protection against infection.
Another type of memory T cell in relation to transplant is CD4 CXCR5 follicular with secondary lymphoid organ. this cell are essential for optimal B cell response and antibody generation . Trm cell are hard to control compare to circulating memory T cell.
Low activation threshold & resistance to conventional costimulating blockade:
Ability of memory T cell to response to lower stimulate antigen and this process important for host defence.
Donor reactive memory T cell can induce allograft rejection despite interruption of essential costimulation pathway CD28 / CD80/ CD86 & CD40 / CD15.
Role of allograft rejection:
CD4 & CD8 memory T cell may lead to allograft rejection in different mechanism.
depletion & suppression of CD8 T cell has significant effects in extend allograft survival. Memory CD4 T cell are hard to control by immunosuppressive agents and can lead to generation of DSA which lead to allantibody mediated graft injury.
recent study in mouse model of heart transplant identify drug to control CD4 independent DSA generation by memory T cell; first gamma interferon secretion by helper T cell is required for de novo DSA generation. second CD40 independent helper function of donor reactive memory CD4 T cell. heart allograft rejection were markedly inhibited by natural B cell activating factors & proliferation induced cytokines & differentiation.
Increase graft cold ischemic promote activation of memory CD8 T cell which lead to rejection.
Influence of memory T cell in allograft tolerance.
presence of memory T cell pretransplant are associated with poor outcome of graft. however presence of EBV / CMV specific memory T cell has not associated with poor outcome of graft.
recent development in targeting alloreactive T cell memory.
Lymphoablation:
it’s used in induction therapy in kidney transplant against donor reactive immunity especially in sensitised patients.
Lymphoablation are target against effector memory T cell.
it’s able to control memory T cell expansion and significant extend heart graft survival in sensitised patients.
alefacept fusion protein which are used in treatment of psoriasis & it may use in future targeting against alloreactive effector memory t cell in organ transplant & bone marrow transplant.
Costimultary blocked:
Belatacept second generation of CTLA4 Ig is used as immunosuppressive agents to prevent allograft rejection & reducing side effects of calcinurine inhibitors but may lead to acute cellular rejection.
Limiting trafficking of alloreactive memory T cell:
show that treatment with Anti leukocyte function associated antigen 1 ( LFA-1) & Anti very late antigen-4 (VLA-4) prolong graft survival in experimental study.
another study treatment with anti LFS-1 inhibit early infiltration of endogenous donor reactive memory CD8 T cell and improve outcome of graft.
Week 1
Journal club
IV. Role of Memory T Cells in Allograft Rejection and Tolerance
Introduction
The importance of this article comes from the fact that in
spite of documented harmful effects of memory T cells in
transplantation, the potential impact of such cells is mostly
neglected while choosing treatment regimens.
Some of the characteristics of memory T cells include:
– Essential elements of allograft rejection process
– Major barrier to tolerance induction in transplant practice
– Commonly associated with poor graft outcome
– Low activation threshold (dangerous in transplant settings)
– Robust effector functions
– Resistance to conventional immunosuppression & co-stimulation blockade.
– Reside in & re-circulate through peripheral non-lymphoid tissues (unlike naïve
T cells).
Alloreactive memory T cells are subdivided according to their origins, phenotypes, & functions:
(i) High affinity alloreactive memory T cell:
– appear when recipients immune system directly exposed to allogenic
MHC molecules.
(ii) Endogenous alloreactive memory T cells:
– no previous exposure to allogenic MCH.
– regularly generated through microbial infections (heterologous immunity).
Origins of Alloreactive Memory T Cells:
– Generated through the recognition of peptides from infectious or environmental antigens presented by self-MHC, which can mimic complexes formed by allogeneic MHC molecules bound to other peptides.
– This antigen mimicry is named “heterologous immunity,” & is well documented in both humans & animal models.
– For example, after an EBV infection, HLA-B8+ persons can be sensitized to the HLA-B4402 molecule through antigen mimicry due to the presentation of viral peptides.
– Transplant recipients can be sensitized from exposures to alloantigens such as previous transplants, pregnancies, & blood transfusions.
– Memory T cells can also homeostatically proliferate in a lymphopenic environment.
– This memory T cells expansion can impair tolerance induction in transplantation.
– Prolonged dialysis vintage & low levels 25-OH-vitamin D in dialysis patients are other factors that lead to expansion of alloreactive memory T.
Memory T cell subsets:
A. Central memory T cells(Tcm):
– express lymphoid homing markers CCR7 & CD62L
B. Effector memory T cells(Tem):
– are CCR7−CD62L− but instead express molecules that
promote migration into peripheral tissues
C. Terminally differentiated effector memory T cells
(Temra):
– re-express naïve T cell surface marker CD45RA
– downregulate expression of CCR7, CD62L, & CD28
– represent a terminal stage of effector differentiation
D. Resident memory T cells(Trm):
– express early activation marker CD69 & αEβ7 integrin
CD103
– do not circulate (reside in peripheral tissues)
– may influence transplant outcome by facilitating GVHD
or allograft rejection.
E. Follicular helper memory T cells(Tfh):
– express CD4+CXCR5
– reside in B cell follicles within secondary lymphoid organs
– essential for optimal B cell responses & antibody generation.
– harder to control than circulating memory T cells (spared by antibody-
mediated lymphoablation)
Role in Allograft Rejection
– memory CD4+ become effector cells upon reactivation.
– provide help for the robust activation of donor-reactive effector CD8+ T cells.
– These effector CD8+ T cells then are the main driving force behind allograft
rejection facilitated by memory CD4+ T cells.
– de novo responses by naïve T cells can be effectively controlled by current
immunosuppression, but memory CD4+ T cells are resistant to these
therapies leading to DSA production & graft injury.
– the presence of memory T cells pre-transplantation is associated with an
increased risk for acute rejection of kidney transplants
RECENT DEVELOPMENTS IN TARGETING ALLOREACTIVE T CELL MEMORY
Lymphoablation
– Memory T cells are the primary targets of induction therapies, but are less
susceptible to depletion than naïve T cells.
– Tem cells are detectable after anti-CD52 mAb or ATG induction & are
associated with acute rejection episodes.
– The efficiency of memory CD4+ T cell depletion is lower than that of CD8+ T
cells.
– Alefacept, a fusion protein combining LFA-3 IgG1, is showing promise for
targeting alloreactive effector/memory T cells in SOT & BMT.
– Apart from direct lymphoablation, manipulating T cell metabolic pathways may
offer a promising therapeutic options.
Costimulatory Blockade
– Belatacept, a CTLA4-Ig, improved graft survival & reduced CNI toxicity in
transplantation.
– However belatacept-treated patients have higher rates of TCMR compared to
CNI treatment.
– Memory T cells are more resistant to CTLA4-Ig effect in animal models, so
possibly pre-sensitized T account for some belatacept-resistant rejection
episodes.
– Increased numbers of both CD4+ & CD8+ CD28− memory T cells are
associated with a poor outcome in renal & lung transplantation.
– CD57+CD4+ T cells are potential mediators of belatacept-resistant renal graft
rejection, are more common in kidney failure, & express high levels of
molecules & cytokines consistent with effector/memory cells (Tem).
– The sensitivity of memory T cells to immunosuppression is dependent on their
origin for example central memory(Tcm) cells with a less differentiated
phenotype were most sensitive to the effects of costimulatory blockade.
– The complexity of costimulatory pathways that control alloimmune responses
must be considered when costimulatory blockade is used in transplantation.
– Attempts to manipulate chemokines &/or their receptors as CCR5 or CXCR3
(so as to prevent memory T cell entrance into graft tissue) didn’t improve
transplant outcome because chemokine/receptor network is redundant.
– However anti-LFA-1mAbs prolonged allograft survival in animal models.
CONCLUSIONS
It is well established that alloreactive memory T cells
accelerate allograft rejection & prevent transplant tolerance.
Several factors hinder the application of emerging
experimental knowledge in transplant practice:
– The diagnostics of T cell allosensitization is problematic.
– Heterogeneity in types & functions of memory T cells, & the need for
additional tests to address this complexity
– Memory T cells in humans are sampled only in peripheral blood, thus skipping
tissue-resident alloreactive memory T cells.
– There are great discrepancies between animal models & human
transplantation.
– Approximating animal models to clinical situation is needed; considering
frequencies of total & donor-reactive memory T cells in different species, cold
ischemia time, & the presence of DSA in recipient serum.
– This will help the development of new strategies to control memory T cells &
improve transplant survival in sensitized recipients.
This article describes the different subsets of alloreactive memory T cells involved in
transplant rejection and examine their generation, functional properties, and mechanisms of action. It also discuss strategies developed to target deleterious allospecifc memory T cells in experimental animal models and clinical settings.
INTRODUCTION:
– Immune responses against previously encountered antigens are benefcial during infections, vaccinations, and tumor surveillance. But, memory immune responses against donor antigens are associated with poor graft outcome.
– Despite well documented harmful effects of memory T cells in transplantation , the potential impact of such cells is mostly neglected while choosing treatment regimens.
– In this review, the characteristics of alloreactive memory T cells and their functions are outlined.
It also describe existing and emerging strategies designed to delete or suppress memory T cells in transplant recipients.
– It discuss future areas of investigation that may translate experimental knowledge of alloreactive memory T cells into clinical practice and thus improve transplant outcome in sensitized recipients.
BASIC BIOLOGY OF ALLOREACTIVE
MEMORY T CeLLS
Origins of Alloreactive Memory T Cells
1. Heterologous immunity:
▪︎ Is well documented in both humans and experimental animal models.
▪︎Occur through the recognition of peptides from commensal bacteria or environmental antigens presented by self-MHC, which can mimic complexes formed
by allogeneic MHC molecules bound to other peptides.
▪︎Can be seen post EBV infection in HLA-B8+ individuals
2. In laboratory mice, direct sensitization with skin allografts or spleen cell.
3. In humans, transplant patients can be sensitized from exposures to alloantigens such as previous transplants, pregnancies, and blood transfusions.
3. Generation through homeostatic proliferation in a lymphopenic environment, including potentially alloreactive and pathogenic T cells. This can impair tolerance induction to allografts.
Note:
The accumulation of alloreactive memory
T cells may be influenced by the end stage organ disease or treatment common
in transplant candidates in these conditions:
i. Prolonged exposure to dialysis
ii. Low serum levels of 25-OH-vitamin D.
Subsets of Memory T Cells:
1) Central memory T cells (Tcm) which express lymphoid homing markers CCR7 and CD62L
2) Effector memory T cells (Tem) are CCR7-CD62L- but instead express molecules that promote migration into peripheral tissues.
Location of Memory T Cells
▪︎ Terminally differentiated effector memory T cells (Temra) re-express naive T cell surface marker CD45RA, while down regulating expression of CCR7, CD62L, and CD28, and represent a terminal stage of effector differentiation.
▪︎Some T cells in peripheral tissues do not circulate and represent a distinct subset of tissue-resident memory T cells (Trm) which:
i. Play an important role in host protection against infections.
ii. May influence transplant outcome by facilitating GVHD or allograft rejection.
▪︎Another important type of memory T cells relevant to transplantation is CD4+CXCR5hi follicular helper (Tf) cells that reside in B cell follicles within secondary lymphoid organs.
▪︎ As memory T cells in secondary lymphoid and non-lymphoid peripheral tissues are spared by antibody-mediated lymphoablation Trm cells may be harder to control compared to
circulating memory T cells.
■Characteristics of memory T cells:
1) Respond to lower antigen doses with limited costimulation,
2) Can induce allograf rejection despite interruption of essential costimulatory pathways.
ROLE OF MEMORY CELLS IN ALLOGRAFT REJECTION
▪︎CD4+ & CD8+ memory T cells subsets contribute to allograf rejection through distinct mechanisms.
▪︎Memory CD4+ T cells not only become effector cells upon reactivation, but
also provide help for the robust activation of donor-reactive effector CD8+ T cells.
▪︎ Allograft rejection is mediated by effector CD8+ T cells and facilitated by memory CD4+ T cells in heart-transplanted mice.
▪︎Memory CD4+ T cells are resistant to immunosuppression therapies and can provide help for the generation of DSA leading to alloantibody-mediated
graf injury.
▪︎Gamma interferon (IFNγ) secretion by memory helper T cells is required for de novo DSA generation.
▪︎Early direct contact of circulating memory CD8+ T cells with donor
endothelium facilitate infltration of recipient leukocytes into the graft.
■INflUENCE OF MEMORY T CELLS ON ALLOGRAFT TOLERANCE
▪︎In laboratory rodents, antigen-induced rather than endogenous memory T cell
prevent transplant tolerance.
▪︎ The vast majority of tolerant animals displayed low frequencies of
donor-reactive memory T cells.
-▪︎lymphoablative approaches targeting memory T cells may interfere with allograft acceptance of certain
types of transplants.
RECENT DEVELOPMENTS IN TARGETING
ALLOREACTIVE T CELL MEMORY
1) LYMPHOABLATION
▪︎Memory T cells are less susceptible to depletion than naïve T cells (T cells with an effector/memory phenotype are detectable after anti-CD52 mAb or ATG induction)
▪︎The efciency of memory CD4+ T cell depletion is generally lower than that of
CD8+ T cells.
▪︎Alefacept, is showing promise for targeting alloreactive effector/memory T cells in solid organ and bone marrow transplantation. Most importantly, pretransplant alefacept therapy synergizes with CTLA4-Ig presumably by targeting costimulatory blockade-resistant CD8+CD2hiCD28- effector/ memory T cells.
2) Costimulatory Blockade
▪︎Belatacept-treated patients have higher rates of acute cellular
rejection compared to CNI treatment.
▪︎Terminally differentiated memory CD4+ and CD8+ T cells in humans (Temra) lose CD28 expression and become in sensitive to the lack of CD28/B7 costimulation.
▪︎Another population of CD57+CD4+ T cells as potential mediators of belatacept-resistant renal allograft rejection. These cells are more common in patients with kidney failure and it downregulate CD28.
●The sensitivity of memory T cells to immunosuppression is dependent on
their origin.
In this mini review authors have focused on impact of memory T cell on transplant outcome.
A very effective and robust immune response against previously exposed antigens is essential for tumor surveillance, immunization and infections however this memory response against donor antigens becomes harmful in case of transplantation and leads to poor graft outcome.response
The authors have also explained the concept of antigenic mimicry . It is likely that these memory cells are generated through the recognition of peptides from commensal bacteria or environmental antigens presented by self-MHC, which can mimic complexes formed by allogeneic MHC molecules bound to other peptides. Such antigen mimicry is named as “heterologous immunity.
Two subsets of memory T cells are recognized.
Central memory T cells which are CCR7 and CD62L positive which reside in lymphoid tissues.
Effector memory T cells are CCR7 and CD62L negative which are in peripheral tissues.
Terminally differentiated effector memory cells re express naïve T cell markers CD45RA
Tissue resident memory T cells do not circulate and are confined to peripheral tissues. Tissue resident memory cells in both lymphoid and non-lymphoid tissue tend to be resistant to destruction by lymphoablation therapies.
Memory T cells can develop a rapid response while re encountering to very low threshold of same antigenThis response takes place even in the presence of co-stimulatory blockade.
Animal studies have shown that both CD4+ and CD8+ memory T cells contribute to allograft rejection through distinct mechanisms.
The authors also explained the concept of influence of memory T cell on allograft tolerance by saying that though memory T cells are generally viewed as pathogenic in the context of transplantation, under certain circumstances they demonstrate regulatory capacity and suppress deleterious pro-inflammatory responses.
Memory T cells are less susceptible to lymphoablation and co stimulation blockade treatment compare to naïve T cells.Memory T cells may still be detectable after induction with anti CD52 or ATG.
In conclusion It is now firmly established that alloreactive memory T cells accelerate allograft rejection and prevent transplant tolerance. However, the implementation of accumulated experimental knowledge in clinical transplantation is impeded by several factors.
1. the diagnostics of T cell allosensitization in transplant candidates is problematic.
2. Memory T cells in humans are sampled only in peripheral blood. So far, there is no information on pathogenicity of tissue-resident alloreactive memory T cells.
3. Memory T cell susceptibility to immu- nosuppression may depend on their origins
4. Finally, despite rapidly accumu- lating data on alloreactive T cell memory, the discrepancies between animal models and transplantation in human patients are profound.
Memory T cells are less susceptible to lymphoablation treatment compare to naïve T cells.
Memory T cells may still be detectable after induction with ant CD52 or ATG.
They also appear to rapidly recover after induction with these agents.
Alefacept is a drug which showing promise in selective targeting of memory T cells and may form part of future treatment approaches.
Immunological memory cells has a unique property
1. It can mount an effective immune response when the stimulus is encountered again.
This response a secondary immune response – is quicker and stronger than the primary response, It takes a smaller stimulus to trigger a secondary response and it occurs even after many years since the first exposure.
2. It has resistance to conventional immunosuppression and costimulation blockade.
Immunological memory is an important mechanism and is one of the decisive factors of successful transplantation process and a major barrier to tolerance induction .
They are currently represented by T and B lymphocytes cells. Among T lymphocytes, memory cells are categories based on their origins, phenotypes, and functions central memory ( express lymphoid homing markers CCR7 and CD62L) , effector memoryCCR7−CD62L− but instead express molecules that promote migration into peripheral tissues) tissue-resident memory( express early activation marker CD69 and αEβ7 integrin CD103 along with a number of tissue-specific chemokine receptors ,The evidence that Trm cells play an important role in transplant outcom and allograft rejection .
Memory T cells can be generated through homeostatic proliferation in a lymphopenic environment, including potentially alloreactive and pathogenic T cells, Such homeostatically expanded memory T cells can impair tolerance induction to allografts.
important type of memory T cells relevant to transplantation are CD4+CXCR5hi follicular helper (Tfh) cells that reside in B cell follicles within secondary lymphoid organs and are essential for optimal B cell responses and antibody generation .
The major cells that participating in allograft rejection are T cells it become effector cells upon reactivation, and also provide help for the strong activation of donor-reactive effector CD8+ T cells . These effector CD8+ T cells are the main driving force behind allograft rejection
Memory CD4+ T cells are resistant to current immunosuppression these and can provide help for the generation of DSA leading to alloantibody-mediated graft injury. Early direct contact of circulating memory CD8+ T cells with donor endothelium upregulates the expression of adhesion molecules and chemokines thus leading to infiltration of recipient leukocytes into the graft ,thus pre transplantation sensitization with T memory cell associated with an increased risk for acute rejection of kidney transplants .
Thanks, Dr Manal
This is much better
Role of Memory T Cells in Allograft Rejection and Tolerance
This paper is a review article on memory T cells highlighting the different subtypes and their role in allograft rejection and tolerance.
Memory T cells are important in our defence against infections, responding to vaccines and in tumour surveillance, however these same cells pose the biggest barrier to solid organ transplantation.
Origins of alloreactive memory T cells
In mice models, exposure to commensal bacteria and environmental antigens leads to establishment of endogenous alloreactive memory T cells.
In humans, sensitization is through exposure to blood transfusion, pregnancy and prior transplantation.
These memory T cells can also be enhanced via homeostatic mechanisms in the lymphopenic state, end stage organ disease or its treatment and vitamin D deficiency.
Location of memory T cells
Two subsets of memory T cells are recognized.
Central memory T cells which are CCR7 and CD62L positive which reside in lymphoid tissues.
Effector memory T cells are CCR7 and CD62L negative which are in peripheral tissues.
Terminally differentiated effector memory cells re express naïve T cell markers CD45RA
Tissue resident memory T cells do not circulate and are confined to peripheral tissues.
Follicular helper T cells (Tfh) are CD4+ CXR5+ are confined to B cell follicles and play a key role in of interacting with B cells and lead to antibody production.
Tissue resident memory cells in both lymphoid and non-lymphoid tissue tend to be resistant to destruction by lymphoablation therapies.
Low activation threshold and resistance to costimulatory blockade
During T cell differentiation, memory T cells acquire the ability to mount rapid response when re -exposed to the same antigen with a very low threshold.
This response takes place even in the presence of co-stimulatory blockade.
Role in Allograft Rejection
Memory CD4+ cells are resistant to current immunosuppressive treatments, which makes them available to generate donor specific antibodies.
Cd4+ T cells are also involved in activation of CD8+ cells.
CD8+ T cells produce adhesion molecules and chemoattractant molecules when they are exposed to donor endothelial cells leading to leucocyte accumulation in the graft.
Long cold ischaemia times appear to enhance the function the activity of CD8+ cells.
Influence on Allograft tolerance
Form animal studies, it appears that endogenous derived memory cells have tolerance properties while memory T cells following antigen stimulation lack tolerance properties.
Targeting alloreactive memory T cells
Lymphoablation
Memory T cells are less susceptible to lymphoablation treatment compare to naïve T cells.
Memory T cells may still be detectable after induction with ant CD52 or ATG.
They also appear to rapidly recover after induction with these agents.
Alefacept is a drug which showing promise in selective targeting of memory T cells and may form part of future treatment approaches.
Costimualtion Blockade
It appears that this approach of selectively blocking costimulatory signals with CTLA4-ig is not an effective strategy in treating transplant patients, as memory cells T cells tend to be resistant to this type of blockade.
This approach also prevents and blocks the function of T regulatory T cells.
Limiting trafficking alloreactive memory T cells
This approach seems to show promise in limiting CD8+ cell infiltration of cardiac allografts and could lead to prolonged graft survival.
Candidate molecules used here include ant Leucocyte function-associated antigen-1 (LFA-1) and very late antigen-4.
In conclusion, this paper has described the different types of memory T cells highlighting their location, functions and how they participate in allograft rejection and tolerance
During an immune response large number of effective lymphocytes are generated but most undergo activation induced cell death- AICD. Few of them survive and give rise to memory T Cells.-Tm. Memory T cells can arise in lymphopenic environment and can affect tolerance to graft. Accumulation of Tm can also be affected by Dialysis, ESRD, low vitamin D levels.
Location of memory T cells
Central– Express CCR and CD62L
Effector– These express CCR7 and CD62L
CD4/CXCR5hi Tfh cells– important in B cell response
These cell have low threshold for activation and resist conventional co stimulatory blockade.
Role in Allograft Rejection
CD4+ provide help in activation of CD8+ cells and also become effector cells which have a important role in rejection. These cell when come in contact with donor endothelium leads to up regulated expression of adhesion molecules and chemokines so as enhancing recipient leukocytes entrance in renal graft.
Role of Memory T cells in allograft tolerance
Memory T cells are related with increased acute rejection ., T cells produced as a result of viral infections may not be related to worse outcomes. These cell may under certain circumstances may provide inflammation suppressing role and providing a lymphoalative therapy in such circumstances many have negative effect on graft acceptance.
Recent developments in targeting alloreactive T cell memory
1-Lymphoablation
Memory T cells are not destroyed by induction therapy. Combination of ATG and co stimulation can give better outcomes like Alfacept. Alfacept inhibits LFA3/CD2 interaction thus blocking T cell activation
2- Co stimulatory Blockade
-Second generation of CTLA4 like Betacept can be used to decrease graft rejection but risk of cellular rejection in increased
3- Limiting Trafficking of alloreactive memory T cells– Drugs which block LFA-1 and VLA4 have shown promising results in experimental models
This paper describes the role of memory T cells in the process of graft tolerance and rejection, describing new and old strategies to suppress the response of these cells in the renal graft.
Sensitization by pregnancy and blood transfusion is much discussed, but viral infections and prolonged exposure to dialysis are also factors of alloantigens.
Células T de memória envolvidas
Costimulation pathways
Some co-stimulation pathways such as CD28/CD80/CD86, ICOS/B7RP-1, CD134/CD134L, CD70/CD27, CD137/CD137L and CD40/CD154 may explain the maintenance of CD4 levels to guarantee immunity against infections in the transplanted individual, concomitant with a decrease in CD8 lymphocytes, increasing graft survival.
Blocking CTLA4-Ig (Belatacept) appears to be a way to minimize the B-lymphocyte-mediated response in graft rejection. The presence of pre-transplant memory T cells is associated with an increased risk of acute graft rejection, which is why the antibody-mediated lymphocyte depletion induction strategy is so popular. Thus, there is a decrease in effector memory B lymphocytes, minimizing the risk of acute rejection. Selective lymphoablation may be a promising strategy in the future.
Conclusions
Thanks Filipe
Please use English rather than Spanish
“Células T de memória envolvidas”
Sorry, my Word changed to Portuguese and I did not change it. I will pay more attention
I thought it is Spanish.
*Early recognition of donor specific antibodies DSA has a feed back in pathway of transplantation and immunosuppressive medication.
Origin of all Alloreactive Memory T cells :
*Heterologous immunity developed when bacteria presented by self-MHC recognise peptides and generates memory cells.
*Previous transplant, pregnancies and blood transfusions ( alloantigens ) are recognised by
memory cells. Alloreactive memory cells also formed on long term dialysis patients.
**Location of memory cells :
*Memory T cells subsets :
1- central memory T cells ( Tcm ) which express lymphoid homing markers CCR7 and CD62L.
2- Effector memory T cells are CCR7- , CD62L-.
3- Tissue- resident memory T cells which plays an important role in host protection against infections.
4- Follicular helper ( Tfh ) cells which is important for optimal B cells response and production of antibodies.
*The ability of memory T cells to respond to low antigen dose can threaten transplant process .
*Circulating memory CD8+ T cells with donor endothelium express adhesive molecules which help in leukocytes infiltration of recipients into graft .
*Pre-transplant Memory T cells are associated with increase risk of acute rejection .
*Memory T cells have low susceptibility for depletion than naiive T cells .
*Detection of memory T cells after induction therapy associated with acute rejection.
*Alfacept is targeting alloreactive effector memory T cells in solid organ and bone marrow transplantation.
*Belatacept which prevents allograft rejection has a higher rate of acute cellular rejection.
*CD57+CD4+T cells mediate belatacept-resistant renal allograft rejection express high levels of CD2 , LFA-1 and VLA-4 and suppress CD28.
CTLA4-Ig inhibits signaling of CTLA-4 which suppress regulatory T cells.
*ICOS/B7RP-1 , CD134/CD134L , CD70/CD27 and CD137/CD 137L inhibition improve graft survival.
*Inhibition of LFA-1 mAbs pre-transplant inhibits endogenous donor-reactive memory CD8+ T cells which in sequence reflected in prolonged graft survival.
References :
1. Augustine JJ, Siu DS, Clemente MJ, Schulak JA, Heeger PS, Hricik DE. Pre- transplant IFN-gamma ELISPOTs are associated with post-transplant renal function in African American renal transplant recipients. Am J Transplant (2005) 5(8):1971–5. doi:10.1111/j.1600-
6143.2005.00958.x
2. Heeger PS, Greenspan NS, Kuhlenschmidt S, Dejelo C, Hricik DE, Schulak JA, et al. Pretransplant frequency of donor-specific, IFN-gamma-producing lymphocytes is a manifestation of immunologic memory and correlates with the risk of posttransplant rejection episodes. JImmunol (1999) 163(4):2267–75.
3. Hricik DE, Rodriguez V, Riley J, Bryan K, Tary-Lehmann M, Greenspan N, et al. Enzyme linked immunosorbent spot (ELISPOT) assay for interferon-gamma independently predicts renal function in kidney transplant recipients. Am J Transplant (2003) 3(7):878–84. doi:10.1034/j.1600-6143.2003.00132.x
4. Poggio ED, Augustine JJ, Clemente M, Danzig JM, Volokh N, Zand MS, et al. Pretransplant cellular alloimmunity as assessed by a panel of reactive T cells assay correlates with acute renal graft rejection. Transplantation (2007) 83(7):847–52. doi:10.1097/01.tp.0000258730.75137.39
5. Lombardi G, Sidhu S, Daly M, Batchelor JR, Makgoba W, Lechler RI. Are primary alloresponses truly primary? Int Immunol (1990) 2(1):9–13.
6. Benichou G, Valujskikh A, Heeger PS. Contributions of direct and indirect T cell alloreactivity during allograft rejection in mice. J Immunol (1999) 162(1):352–8.
7. Benichou G. Direct and indirect antigen recognition: the pathways to allograft immune rejection. Front Biosci (1999) 4:D476–80.
8. Lechler R, Lombardi G. Structural aspects of allorecognition. Curr Opin Immunol (1991) 3(5):715–21.
9. Mbitikon-Kobo FM, Vocanson M, Michallet MC, Tomkowiak M, Cottalorda A, Angelov GS, et al. Characterization of a CD44/CD122int memory CD8 T cell subset generated under sterile inflammatory conditions. J Immunol (2009) 182(6):3846–54. doi:10.4049/jimmunol.0802438
Thanks
No need for references
Memory T cells accelerate graft rejection and prevent transplant tolerance
Basic biology of alloreactive memory T cells
Origin: :
Location:
Low activation threshold and resistant to conventional costimulatory blockade:
They respond to low antigen doses with limited costimulation making them more dangerous in transplant.
Role in allograft rejection:
Influence on allograft tolerance:
Presence of memory T cells pre transplant is associated with increased risk of acute rejection. However, some studies showed that under certain circumstances, memory T cells have regulatory capacity and decrease pro-inflammatory immune response.
Recent developments in targeting alloreactive memory T cells:
Lymphoablation:
Costimulatory blockade:
Belatacept
CD40/CD154 is another major costimulatory pathway attempted to be blocked but resulted in thromboembolic effects.
Limiting trafficking of alloreactive memory T cells:
Attempts to neutralize chemokines and chemokine receptors didn’t meet the expectations.
Limitations to target memory T cells in clinical transplantation:
The heterogenicity in phenotype and functions of memory T cells
memory T cells are sampled from peripheral blood without information about tissue resident T cells
Sensitivity of T memory cells to immunosuppression depends on its origin which can’t be traced.
Major differences between human and animal models.
Thanks
Alloreactive memory T cells represent an essential element of the allograft rejection process and a major barrier to tolerance induction in clinical transplantation. This article describes the different subsets of alloreactive memory T cells involved in transplant rejection and examine their generation, functional properties, and mechanisms of action.
CD4 + and CD 8+ T cells work together in the activation of donor-reactive: generation of DSA leading to alloantibody-mediated graft injury, endothelium upregulates the expression of adhesion molecules and chemokines, secretion gamma interferon, upregulate the expression of ICOS;
Some characteristics are important in the performance of memory T cells:
1 – alloreactive memory T cells may be sensitized from exposures to alloantigens such as previous transplants, pregnancies, and blood transfusions. There are also other important situations such as: homeostatic proliferation in a lymphopenic environment, end stage organ disease or treatment common in transplant candidates;
2 – location of memory T cells in : Central X peripheral tissues (Tem and yours subset : Temra and Trm). Where the existence of peripheral T cells may influence transplant outcome facilitated by GVHD or allograft rejection.
3 – Memory T cells has the ability to respond to lower antigen doses with limited costimulation, because T cell receptor and costimulatory signaling cascades are adjusted to ensure rapid activation of high magnitude.
4 – Memory T cells are less susceptible to antibody-mediated lymphocyte depletion, as well as costimulatory blockade with Belacept. But, assays demonstrated that the sensitivity of memory T cells to immunosuppression is dependent on their origin and others costimulatorys are involved, enabling the action of immunosuppressants such as: tacrolimus, mAb inhibits proliferation and others
Despite the information above, there are impediments to implementing protocols based on existing experimental knowledge, due to the following factors:
1 – the diagnostics of T cell allosensitization in transplant candidates is problematic, because to heterogeneity in phenotype and functions of memory T cells, complementary tests will be required including analyses of cytokine producing, cytotoxic, and follicular helper T cells ;
2 – memory T cells in humans are sampled only in peripheral blood. So far, there is no information on pathogenicity of tissue-resident alloreactive memory T cells;
3 – memory T cell susceptibility to immu[1]nosuppression may depend on their origins. As immunological histories of individuals are difficult to trace, the situation may arise when patients with similar T cell memory profile require distinct treatment strategies
Thanks
Origin of alloreactive memory T cells:
In mice, memory T cells constitute around 5-10% of all T cells. In the absence of prior exposure to antigens, only 1-10% can react to allogeneic MHC, the source of these memory cells is infection and exposure to environmental antigens ( heterologous immunity).
Memory T cells can also be generated through homeostatic proliferation in a lymphopenic environment and can impair tolerance to allografts.
The accumulation of these memory cells can be affected by the end-organ disease such as in patients with ESRD, prolonged exposure to dialysis & the low level of 25 OH-vitamin D in these patients lead to the development of memory cells.
Location of memory T cells:
Memory T cells are characterized by a low activation threshold and resistance to costimulatory blockade and this results in the ability of memory T cells to respond to lower antigen doses with limited costimulation.
Role in allograft rejection:
Upon activation of memory CD4+ T cells, they become effector cells & also provide help for the activation process of CD8+ T cells. These effector CD8+ T cells are the main driving force for rejection. Early direct contact of these cells with donor endothelium upregulates the expression of adhesion molecules and chemokines thus facilitating infiltration of the recipient leukocytes into the graft.
Memory CD4+ T cells are resistant to immunosuppressive medications and can provide help for DSA formation & ABMR.
Influence of memory T cells on allograft tolerance:
The presence of memory T cells pretransplantation has been associated with an increased risk of acute rejection, however, there is no indication that the presence of heterologous immunity( such as EBV, CMV-specific memory T cells) correlates with worse graft outcomes.
Under certain circumstances, memory T cells show a regulatory effect and suppress the pro-inflammatory immune response and there is concern about the lymphoablative approaches targeting memory T cells may interfere with allograft acceptance of certain types of transplants.
Recent developments in targeting alloreactive T cell memory
Thanks
Introduction ;
Memory T cells a component of immune system that requires minimal threshold for activation, mounts strong immune response upon re-exposure to the same antigen. They are also resistant to standard immune-suppression and co-stimulation blockade. This later effects are dangerous in transplantation
Basic Biology of allo-reactive memory T cells ;
Origin of allo-reactive memory T cells ;
Location of memory T cells ;
Low Activation of Threshold and Resistance to Conventional Co-stimulatory Blockade ;
Contribution of memory T cells to allograft rejection & tolerances ;
Role in allograft rejection ;
Influence of Memory T cells on Allograft Tolerance ;
Recent Developments in Targeting Alloreactive T cell memory ;
Lymphoablation ;
Costimuatory Blockade ;
Limiting Trafficking of allo-reactive Memory T cells ; Anti-LFA-1(Leukocytes Function Associated Antigen-1) and anti-VLA-4( Very Late Antigen 4) were associated with improve graft survival in experimental models 133.
Concluding Remarks ; some challenges in transplantation includes
Thanks
Role of memory T cells in allograft rejection and tolerance.
Rapid response of Memory T cells is considered double edged sword as its beneficial when occurred with infection, vaccination and tumor surveillance , but when response occurred due to donor antigen so, its associated with high risk of rejection and poor graft outcome.
BASIC BIOLOGY OF ALLOREACTIVE MEMORY T CELLS.
Origins of Alloreactive Memory T Cells:
Memory T cells can be generated after recognition of protein peptides of pathogens(viral, bacterial, etc.),which structurally resembling the allogenic MHC molecule which is called “heterologous immunity,”
For example, following an EBV infection, HLA-B8+ individuals is sensitized to the allo-MHC molecule HLA-B4402 through antigen mimicry .
The transplant patients can be sensitized from exposures to alloantigen such as previous transplants, pregnancies, and blood transfusions so they have high titer of memory T cells and also Memory T cells increasing with patients on dialysis for long period.
Location of Memory T Cells:
Central memory T cells (Tcm) :express markers CCR7 and CD62L and effector memory T cells (Tem) in peripheral tissue.
Tissue-resident memory T cells (Trm)which are T cells in peripheral tissues do not circulate (so, its harder to control compared to circulating memory T cells)and play an important role in host protection against infections, but has a role in transplant outcome by facilitating GVHD or allograft rejection.
The follicular helper (Tfh) cells located in B cell follicles within secondary lymphoid organs and are essential B cell responses and antibody generation .
Low Activation Threshold and Resistance to Conventional Costimulatory Blockade:
Memory T cells are programmed during differentiation to be rapid active of high level with antigen reencounter and respond to lower antigenicity which is good in body defense but this induce graft rejection in transplant despite using costimulatory blockade.
CONTRIBUTION OF MEMORY T CELLS TO ALLOGRAFT REJECTION AND TOLERANCE:
Memory CD 4 T cell has a role in reactivation and also help donor-reactive effector CD8+ T cells which play a major role in allograft rejection so decreasing or depleting of effector CD8+ T increase graft survival.
CD 4 T cell help for the generation of DSA leading to alloantibody-mediated graft injury and unfortunately resistant to current immunosuppression.
Direct contact of circulating memory CD8+ T cells with donor endothelium upregulates the expression of adhesion molecules and chemokines thus facilitating infiltration of recipient leukocytes into the graft which increase risk of rejection and prolonged cold ischemia aggravate this cascade.
Influence of Memory T Cells on Allograft Tolerance.
The presence of memory T cells pre-transplantation are associated with an increased risk for acute rejection of kidney transplant but “heterologous immunity” in transplant recipients doesn’t correlates with worse graft outcomes ,so lymph ablative approaches targeting memory T cells may interfere with allograft acceptance of certain types of transplants.
RECENT DEVELOPMENTS IN TARGETING
ALLOREACTIVE T CELL MEMORY
Lymphoablation:
One of the most important strategy in sensitized recipients is induction therapy by ATG or alemtuzumab which is directed mainly to Memory T cells but its efficacy is less than naïve T cell.
Alefacept, a fusion protein which binds to CD2which is expressed on effector/memory T cells and depleting them so its used for targeting
costimulatory blockade-resistant CD8+CD2hiCD28 effector/memory T cells as coeffect for CTLA4-Ig .
Costimulatory Blockade
Belatacept, a second generation of CTLA4-Ig, is currently used in clinical transplantation to prevent allograft rejection but terminally differentiated memory CD4+ and CD8+ T cells in humans (Temra) lose CD28 expression so become insensitive to CTLA4-Ig due to the lack of CD28/B7 co-stimulation.
Limiting Trafficking of Alloreactive Memory T Cells.
By using the integrin blockade like anti-LFA-1 or anti-VLA-4 blocking mAbs especially with costimulatory blockade-resistant rejection by memory CD8+ T but still need further studies.
Thanks
In the modern era of potent immunosuppression, acute rejection remains a great obstacle for the short and long term preservation of kidney function.
The preformed memory T cells against allograft antigens are associated with increased risk of acute rejection and allograft failure.
Memory T cells are well known or their low activation threshold, aggressive inflammatory functions, and resistance to conventional immunosuppression and co-stimulation blockade.
Memory T cells have protective effects against infection and tumors. They are also responsible for long term protection against infection through vaccination. This protective effect against infection or malignancy is considered detrimental in the setting of transplantation. Activation of memory T cells is associated with T cell mediated activation of B cells with subsequent production of donor specific antibodies and eventually acute antibody mediated rejection. AMR is commonly associated with poor graft outcome.
Memory T cells are classically divided into two major groups.
Central memory T cells (Tcm) markers CCR7 and CD62L, whereas effector memory T cells (Tem) are CCR7−CD62L− .T em express molecules that promote migration into peripheral tissues. Another type of T cells in humans called terminally differentiated effector memory T cells (Temra) express naive T cell surface marker CD45RA, while downregulating expression of CCR7, CD62L, and CD28, and represent a terminal stage of effector differentiation.
Several studies during the past decade have investigated the role of CD4+ and CD8+ memory T cells in acute rejection and showed that these subsets contribute to allograft. Indeed, memory CD4+ T cells not only become effector cells upon reactivation, but also provide help for the robust activation of donor-reactive effector CD8+ T cells.
Current immunosuppression can efficiently control de novo responses by naïve T cells, however memory CD4+ T cells are resistant to immunosuppression and can activate B cell response and generation of DSA leading to alloantibody-mediated graft injury.
T memory cells can demonstrate regulatory capacity and suppress deleterious pro-inflammatory immune responses, although memory T cells are generally viewed as pathogenic in the context of transplantation.
Therapies that was used to target memory cells include lymphoablation, costimulatory blockade and integrin blockade.
The most commonly used induction regimen in high risk patients include drugs that aim to block t cell response. Antibody-mediated lymphocyte depletion of t cells include monoclonal and polyclonal antibodies.
Although memory T cells are the primary targets of induction therapies, they are less susceptible to depletion than naïve T cells. The efficiency of memory CD4+ T cell depletion is generally lower than that of CD8+ T cells. Additional depletion of residual CD4+ T cells severely impairs the recovery of memory CD8+ T cells after ATG treatment.
Costimulatory pathways have been also the target of blockade, as Belatacept does.
Belatacept, B7 inhibitor, is currently used in clinical transplantation to prevent allograft rejection and minimize nephrotoxic effect of CNI. Memory T cells are more resistant to the effects of CTLA4-Ig in animal transplantation models,that’s why patients treated with belatacept have higher rates of acute cellular rejection compared to CNI treated group,but have reduced side effects and improved graft survival. it is possible that presensitized T cells could account for some belatacept-resistant rejection episodes.
In addition to blocking CD28/B7 costimulation, CTLA4-Ig also prevents signaling through CTLA-4, which can have negative effects on generation and functions of regulatory T cells (Tregs).
Another way for blockade of T cell activation is the use of integrin blockade. Findings in some studies suggested that a short course of integrin blockade may be effective in controlling T cell memory while avoiding side effects of long-term treatments. Reagents blocking LFA-1 and VLA-4 have been demonstrated to prolong allograft survival in experimental transplantation.
very well demonstrated and understood
clear explanation of:
increased incidence of TCR with CTLA-4Ab despite less side effects of CNIs
relation with Tregs
Differential effect of ATG on both cells
WELLDONE
your summary is useful to the rest of the group.
Memory T cells exhibit the following criteria :
Types of memory T cells
Memory cells to HLA antigens may be preformed due to pregnancy, previous blood transfusions or previous transplantations, or may arise after transplantation.
Why memory cells are important in renal transplantation
1. Memory cells has lower activation threshold and persist for long time when compared to naive cells
2. Memory cells are resistant to costimulation signals that mean they require lower costimulatory signals for being recalled
3. Memory cells are resistant to regulatory T cells
4. They are not suppressed by conventional immunosuppressive drugs
5. Highly resistance to induction of tolerance
thus alloreactive memory cells constitute a significant challenge when transplanting a foreign graft.
Curently transplantation is depending on negative cross match between donor and recipient and HLA matching , but this may be misleading as it ignores the rule of memory cells in future graft rejection. thus traditional immunosuppression may has good effect on short term graft survival, but long term graft survival may be lower due to memory cells
Mechanism of rejection by memory cells
Rejection occurs either due to Alloantigen-dependent or alloantigen-independent factors (tissue injury such as ischemic injury leading to upregulation of expression of adhesion molecules, or shedding of intact HLA )
Either Allo-antigen independent or dependent factors activate the immune response in the following way:
1- Donor-reactive memory CD4+ T cells are 2 types T helper 1 that activate macrophage leading to delayed type hypersensitivity and T helper 2 that provide help to B cells leading to trasnformation of B cells to plasma cells that produce DSA.
2- Alloreactive CD8-positive T cells that produce cell-mediated cytotoxicity (kill the cell or induced apoptosis)
Two-signal are required for T cell activation
· Signal 1 occur when antigen peptide- MHC complex located on APC is attached to TCR
· Signal 2 occur when one or more TCR antigens (CD28, CTLA-4) interacts with its specific legand in APC (B7-1, B7-2). this is called costimulation, CD28 stimulate, while CTLA-4 supress T cells
Interventions that target memory T cells
1- Lymphoablation by depleting T cells using ATG, ATG cause depletion of T cells, although ATG induced lymphopenia triger generation of alloreactive memory T cells, but it was found that ATG significantly increase T regulatory cells which supress memory T cells, So better survival of graft was obtained by ATG induction
2- Co-stimulation blockade , Abatacept (CTLA4-Ig) is still under trial but it was found that the use of abatacept is associated with inhibition of T helper 1 and not T helper 2, leading to decrease in the incidence of acute rejection, but chronic rejection still occurs
Belatacept (a high affenity variant CTLA4-Ig), has been developed with more immunosuppressive effect
welldone
good you mentioned there are both memory T and B cells.
Role of memory T-cells in organ transplantation :
1- Memory T-cells are a small subgroup of T- lymphocytes. However, unlike
their native counterparts, memory T- cells reside and recirculate through non-lymphoid tissues.
2- They are classified into different categories, based on their origin, phenotype and function
3- They are generated by previous allo-antigen exposure as with previous blood transfusion, organ transplantation, pregnancy or previous infections.
1- Central : they are expressing CCR7 and CD62L.
2- Effector : they are expressing molecules that promote migration into peripheral tissues.
these cells are largely involved in accelerating allograft rejection and prevention of immune tolerance, which is the hopeful current and future target in the field of solid organ transplantation. Currently, memory T-cells are the target of many therapeutic approaches.
1- Lymphoablation : By induction therapy. However, memory T- cells are less susceptible to treatment than naive T-cells.
2- Co-stimulation blockade : By Belatacept. there was a reported decrease in side effects of maintenance immunosuppression but unfortunately, there was an increase in the incidence of acute cellular rejection.
3- Limiting trafficking by a short course of integrin blockade.
1- Diagnostics of T- cell allosensitization is problematic due to significant variations in memory T- cells functions and phenotypes. Therefore, complementary tests are needed and the resulting information is complex.
2- Memory T-cells are sampled only in peripheral blood, so no information on pathogenicity of tissue-resident cells is clearly available.
3- The discrepancies between animal transplantation models and transplantation in human are profound.
thankyou for the conclusion.
Memory b cells, alloantibodies and innate immune response affects the transplant outcome. Also, memory T cells have harmful effect on transplant but their impact is neglected in choosing treatment regimens
.
Transplant patients can be sensitized from exposures to alloantigens such as previous transplants, pregnancies, and blood transfusions
Location of Memory T Cells and types
There is various types of memory T cells, including
Tissue resident memory T cells (Trm): Do not circulate in blood -indicated by their name- express early activation marker CD69 and αEβ7 integrin CD103 along with a number of tissue-specific chemokine receptor. They are spared by antibody mediated lymphoablation and harder to control than circulating memory T cells. Trm cells of the donor facilitate GVHD and from recepirnt facilitate allograft rejection.
Central memory T cells (Tcm) express lymphoid homing markers CCR7 and CD62L, whereas effector memory T cells (Tem) are CCR7−CD62L− but instead express molecules that promote migration into peripheral tissues
terminally differentiated effector memory T cells (Temra) reexpress naive T cell surface marker CD45RA, while downregulating expression of CCR7, CD62L, and CD28, and represent a terminal stage of effector differentiation
Another important type of memory T cells relevant to transplantation is CD4+CXCR5hi follicular helper (Tfh) cells that reside in B cell follicles within secondary lymphoid organs and are essential for optimal B cell responses and antibody generation
Low Activation Threshold and Resistance to Conventional Costimulatory Blockade
Memory T cell are responsible for the rapid activation and high response once antigen is encountered. This is an important process for immunological defenses but in transplant patients it makes alloreactive memory T cells dangerous to the transplant.
Numerous studies in animal models have demonstrated that donor-reactive memory T cells can induce allograft rejection despite interruption of essential costimulatory pathways, CD28/CD80/CD86 and CD40/CD154
CONTRIBUTION OF MEMORY T CELLS TO ALLOGRAFT REJECTION AND TOLERANCE
Role in Allograft Rejection
Memory CD4+ T cells become effector cells once reactivated and also cause enormous activation of donor reactive effectors CD8+ T cells – which then constitute as the main force for allograft rejection-. The main problem is, unloke naïve T cells, these CD4+ T cells are resistant to conventional immunosupressants and lead to the generation of DSA and alloantibody mediated graft injury.
Influence of Memory T Cells on Allograft Tolerance
presence of memory T cells pretransplantation has been associated with an increased risk for acute rejection of kidney transplants. However, while EBV- and CMV-specific memory T cells displaying alloreactivity have been detected in human transplant recipients, so far there is no indication that the presence of “heterologous immunity” in transplant recipients correlates with worse graft outcomes.
RECENT DEVELOPMENTS IN TARGETING ALLOREACTIVE T CELL MEMORY
Lymphoablation
Induction therapy is widely used in clinical transplantation to overcome the deleterious effects of preexisting donor-reactive immunity. Antibody-mediated lymphocyte depletion is most commonly used induction strategy, particularly in highly sensitized patients and in patients receiving marginal grafts
Alefacept, a fusion protein combining extracellular domain of LFA-3 with constant regions of human IgG1. Alefacept is currently being used in clinic for the treatment of severe psoriasis and is showing promise for targeting alloreactive effector/memory T cells in solid organ and bone marrow transplantation
Costimulatory Blockade
Belatacept, a second generation of CTLA4-Ig, is currently used in clinical transplantation to prevent allograft rejection and minimize the toxic side effects of calcineurin inhibitors, bit still belatacept treated patients have higher rates of acute cellular rejection compared to CNI treatment.
CONCLUDING REMARKS
The diagnostics of T cell allosensitization in transplant candidates is problematic. Due to heterogeneity in phenotype and functions of memory T cells, complementary tests will be required including analyses of cytokine producing, cytotoxic, and follicular helper T cells
Memory T cells in humans are sampled only in peripheral blood. So far, there is no information on pathogenicity of tissue-resident alloreactive memory T cells.
Memory T cell susceptibility to immunosuppression may depend on their origins. As immunological histories of individuals are difficult to trace, the situation may arise when patients with similar T cell memory profile require distinct treatment strategies.
Despite rapidly accumulating data on alloreactive T cell memory, the discrepancies between animal models and transplantation in human patients are profound.
well understood final summary is efficiantly clarifying. thankyou
Role-of-Memory-T-Cells-in-Allograft-Rejection-and-Tolerance
Alloreactive memory T cells represent an essential element of the allograft rejection process and a major barrier to tolerance induction in clinical transplantation.
This article describes the different subsets of alloreactive memory T cells involved in transplant rejection and examine their generation, functional properties, and mechanisms of action.
Basic biology OF alloreactive memory T cells
Origins of Alloreactive Memory T Cells
In humans, transplant patients can be sensitized from exposures to alloantigens such as previous transplants, pregnancies, and blood transfusions. Until now, only memory T cells recognizing intact alloantigens directly have been reported. Yet, it is probable that sensitized patients exhibiting high titers of allospecific antibodies display memory T cells
recognizing alloantigens indirectly as donor peptides–self-MHC complexes.
Memory T cells can also be generated through homeostatic proliferation in a lymphopenic environment, including potentially alloreactive and pathogenic T cells. Such homeostatically expanded memory T cells can impair tolerance induction to allografts.
The accumulation of alloreactive memory T cells may be influenced by the end stage organ disease or treatment common in transplant candidates. For example, prolonged exposure to dialysis increases the risk of developing alloreactive memory T cells. In addition, low serum levels of 25-OH-vitamin D in dialysis patients correlates with the frequency of alloreactive memory T cells independent of age, gender, previous transplants, or time on dialysis.
Location and types of Memory T Cells
Memory T cells have been traditionally divided into two major subsets with largely overlapping functions but distinct trafficking patterns
– Central memory T cells (Tcm) express lymphoid homing markers CCR7 and CD62L.
– effector memory T cells (Tem) are CCR7−CD62L− but instead express molecules that promote migration into peripheral tissues.
– In humans, but not in mice, some memory T cells [terminally differentiated effector memory T cells (Temra)] reexpress naive T cell surface marker CD45RA, while downregulating expression of CCR7, CD62L, and CD28, and represent a terminal stage of effector differentiation
– some T cells in peripheral tissues do not circulate and represent a distinct subset of tissue-resident memory T cells (Trm). Trm cells express early activation marker CD69 and αEβ7 integrin CD103 along with a number of tissue-specific chemokine receptors. There is accumulating evidence that Trm cells play an important role in host protection against infections. It is conceivable that Trm cells of both donor and recipient origins may influence transplant outcome by facilitating GVHD or allograft rejection respectively.
– Another important type of memory T cells relevant to transplantation is CD4+CXCR5hi follicular helper (Tfh) cells that reside in B cell follicles within secondary lymphoid organs and are essential for optimal B cell responses and antibody generation
Contribution OF memory T cells TO allograft rejection and
tolerance
A) Role in Allograft Rejection
During the past decade, studies investigating CD4+ versus CD8+ memory T cells revealed that these subsets contribute to allograft rejection through distinct mechanisms. Indeed, memory CD4+ T cells not only become effector cells upon reactivation, but also provide help for the robust activation of donor-reactive effector CD8+ T cells. These effector CD8+ T cells then are the main driving force behind allograft rejection facilitated by memory CD4+ T cells.
While de novo responses by naïve T cells can be efficiently controlled by current immunosuppression, memory CD4+ T cells are resistant to these therapies and can provide help for the generation of DSA leading to alloantibody-mediated graft injury
Early direct contact of circulating memory CD8+ T cells with donor endothelium upregulates the expression of adhesion molecules and chemokines thus facilitating infiltration of recipient leukocytes into the graft.
The approximation of clinical situation by increasing graft cold ischemia storage time enhanced effector functions of endogenous memory CD8+ T cells enabling them to promptly reject a cardiac allograft despite costimulatory blockade with CTLA4-Ig.
B) influence of Memory T Cells on Allograft Tolerance
The presence of memory T cells has been often correlated with poor outcomes in clinical transplantation. In humans, the presence of memory T cells pretransplantation has been associated with an increased risk for acute rejection of kidney transplants. However, while EBV- and CMV-specific memory T cells displaying alloreactivity have been detected in human transplant recipients, so far there is no indication that the presence of
“heterologous immunity” in transplant recipients correlates with worse graft outcomes.
Even though memory T cells are generally viewed as pathogenic in the context of transplantation, under certain circumstances, they demonstrate regulatory capacity and suppress deleterious pro-inflammatory immune responses
Recent developments in targeting alloreactive T cell memory
A) Lymphoablation
Induction therapy is widely used in clinical transplantation to overcome the deleterious effects of preexisting donor-reactive immunity. Antibody-mediated lymphocyte depletion is most commonly used induction strategy, particularly in highly sensitized patients and in patients receiving marginal grafts.
Although memory T cells are the primary targets of induction therapies, they are less susceptible to depletion than naïve T cells. The efficiency of memory CD4+ T cell depletion is generally lower than that of CD8+ T cells.
Alefacept is currently being used in clinic for the treatment of severe psoriasis (89, 90) and is showing promise for targeting alloreactive effector/memory T cells in solid organ and bone marrow transplantation (91–95). Most importantly, pretransplant alefacept
therapy synergizes with CTLA4-Ig presumably by targeting costimulatory blockade-resistant CD8+CD2hiCD28- effector/ memory T cells
B) Costimulatory Blockade
Belatacept, a second generation of CTLA4-Ig, is currently used in clinical transplantation to prevent allograft rejection and minimize the toxic side effects of calcineurin inhibitors.
Despite reduced side effects and improved graft survival, belatacept-treated patients have higher rates of acute cellular rejection compared to CNI treatment.
C) Limiting Trafficking of Alloreactive Memory T Cells
pretransplant treatment with anti-LFA-1 mAbs inhibited early infiltration of endogenous donor-reactive memory CD8+ T cells into cardiac allografts, and significantly
prolonged allograft survival (135). These findings suggest that a short course of integrin blockade may be instrumental in controlling T cell memory while avoiding side effects of long-term treatments.
welldone
Origin of allograft reactive memory T cells
They arise by identification of peptides from commensal bacteria or antigens presented by self-MHC, similar to complexes formed by allogeneic MHC molecules bound to other peptides leading to heterologous immunity .
Transplant patients can be sensitized through previous transplants, pregnancies, and blood transfusions.
Alloreactive memory T cells risk was higher in patients with prolonged dialysis periods.
It was published that low serum levels of 25-OH-vitamin D independently in dialysis patients correlates with the frequency of alloreactive memory T cells.
Memory T cell location
Central T cells expresses CCR7 and CD62L, whereas and T cell effector memory T cells (Tem) express CCR7−CD62L
Trm cells has a defensive role against infections. It facilitates GVHD or allograft rejection thereby affecting graft survival.
CD4+CXCR5hi follicular helper (Tfh) cells within secondary lymphoid organs , are essential for B cell responses and antibody production.
Low stimulation threshold and resistance to costimulatory blockage
memory T cells can respond to lower antigen doses with limited costimulation,leading to graft rejection.
Role in allograft rejection
CD4 T h cells as well as its role in rejection it activates CD 8 T h cells. Memory CD4+ T cells evoke DSA by producing gamma interferon (IFNγ) secretion .
Increasing graft cold ischemia storage time enable memory CD8+ T cells rejection of a cardiac allograft despite costimulatory blockade with CTLA4-Ig.
Although memory T cells have negative drawbacks in the transplantation, they have regulatory capacity and suppress deleterious pro-inflammatory immune responses.
Shedding light that lymphoablative approaches targeting memory T cells can affect allograft tolerance in some transplants.
Lymphoablation
Induction therapy uses Antibody-mediated lymphocyte depletion , specifically with highly sensitized recepients.
In rodents, after induction therapy with ATG prexisting memory T cells rapidly reoccur .The CD8+ T cells depletion is more efficient than memory CD4+ T cell depletion.
Alefacept targets alloreactive effector/memory T cells in solid organ and bone marrow transplantation . It synergizes with CTLA4-Ig by targeting costimulatory blockade-resistant CD8+CD2hiCD28− effector/ memory T cells.
Costimulatory Blockade
Belatacept, a second generation of CTLA4-Ig, used to prevent allograft rejection and has lesser side effects than calcineurin inhibitors on the other side incidence of cellular rejection is higher than with CNI.
Limiting Trafficking of Alloreactive Memory T Cells
a short course of integrin blockade can control T cell memory and at the same time avoiding side effects of long-term treatments.
please revise the references for relation of CD4+T and DSAs the effect has to be via B cells.
otherwise fine summary.
Role of Memory T Cells in Allograft Rejection and Tolerance
In the absence of prior exposure to alloan- tigens, 1–10% of these memory T cells can react to allogeneic major histocompatibility complex (MHC) molecules.
these cells called endogenous or natural alloreac- tive memory T cells recognize intact allogeneic MHC molecules through the direct allorecognition pathway .
these memory cells are generated through the recognition of peptides from commensal bacteria or environmental antigens presented by self-MHC, which can mimic complexes formed by allogeneic MHC molecules bound to other peptides.
Such antigen mimicry, named “heterologous immunity.
Ex – following an EBV infection, HLA-B8+ individuals can become sensitized to the allo-MHC molecule HLA-B4402 through antigen mimicry resulting from the presentation of some viral or parasitic peptides.
prolonged exposure to dialysis increases the risk of developing alloreactive memory T cells.
low serum levels of 25-OH-vitamin D in dialysis patients correlates with the frequency of alloreactive memory T cells independent of age, gender, previous transplants, or time on dialysis .
Location of Memory T Cells-
Central memory T cells
effector memory T cells
memory T cells in secondary lymphoid and non-lymphoid peripheral tissues are spared by antibody-mediated lymphoablation Trm cells may be harder to control compared to circulating memory T cells.
memory T cells to respond to lower antigen doses with limited costimulation, i.e., to antigen presented by non-professional antigen-presenting cells .
memory CD4+ T cells not only become effector cells upon reactivation, but also provide help for the robust activation of donor-reactive effector CD8+ T cells (40). These effector CD8+ T cells then are the main driving force behind allograft rejection facilitated by memory CD4+ T cells.
Memory T cells under certain circumstances demonstrate regulatory capacity and suppress deleterious pro-inflammatory immune responses.
Recent developments –
Lymphoablation
Using ATG
Alefacept, a fusion protein combining extracellular domain of LFA-3 with constant regions of human IgG1.
Co stimulatory blockade
Belatacept, a second generation of CTLA4-Ig.
terminally differentiated memory CD4+ and CD8+ T cells in humans (Temra) lose CD28 expression and become insensitive to the lack of CD28/B7 costimulation.
Limiting Trafficking of Alloreactive Memory T Cells
Using LFA-1 and VLA-4 blocking abs.