There are 5 subtypes of Treg : natural Treg( nTreg), inducible Treg( iTreg), IL-10 producing type I( TrI, CD8+ Treg, and IL-17 producing Treg.
nTreg form 5-10% of total peripheral T cells & it is stable population can maintain peripheral tolerance & prevent autoimmunity while iTreg can loss its expression of Foxp3 during withdrawal of TGF-B so retain cell phenotype similar to conventional CD4Tcells.
ATG, Alemtuzumab & mTOR inhibitor all can potentiate the tolerance function of Treg.
Number of lymphocytes with regulatory function are present;
regulatory B cells, IL-10+ Foxp3− regulatory CD4+ T cells (Tr1), regulatory CD8+ T cells, and
Foxp3+ regulatory CD4+ T cells which play major role in maintaining immune homeostasis and graft tolerance so preservation of Treg function will be a key to successfull ong-term graft survival without rejection episodes
three Treg subsets have been described in mice and humans: central Treg (cTreg; also referred to as naïve-like or resting Treg), effector Treg (eTreg; also referred to as activated Treg), and memory Treg (mTreg.
T reg cells are subtype of T lymphocytes
It expresses CD4, CD25, and FOXP3 on it surfce it is major player in the immune tolerance .
Tregs comprise 5–10% of peripheral CD4+ T cells in the circulation.
And it can suppress different types of T cells initially known to suppress CD4+CD25− T cells Recently, Tregs have been implicated in the regulation of other cells in adaptive immune system including CD8+ T cells and B cells .
Tregs also regulate the function of cells of the innate immune system like macrophages, dendritic cells, and neutrophils .
Another type of Treg cells is called IL-10-producing T regulatory type 1 (Tr1) cells they usually do not express FOXP3 and have been shown to have strong suppressive ability .
Tr1 cells are able to inhibit CD4+ T cell responses through IL-10 dependent and independent mechanisms .
Importantly, Tr1 cells are distinct from FOXP3+ Tregs (natural Tregs) because they do not constitutively express FOXP3. Also, Tr1 cells have been shown to function separately from FOXP3+ Tregs in certain conditions.
Grazia Roncarolo M, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev. (2006) 212:28–50.
Vieira PL, Christensen JR, Minaee S, O’Neill EJ, Barrat FJ, Boonstra A, et al. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol. (2004) 172:5986–93.
What are the immunosuprressive medications that potentiate the tolerance function of Treg?
The immunosuppressive drugs from the mTOR inhibitor class (i.e. rapamycin and everolimus) bind to FKBP12 (FK506 binding protein 12) and suppresses mTORc1.
rapamycin was shown to maintain or to promote human Treg expansion and function.
rapamycin also stabilized Foxp3 transcripts and prolonged half-life of adoptively transferred Tregs in rhesus macaques, compared to no treatment .
Among immunosuppressive drugs, rapamycin stands out as having the most benefits in sparing or promoting Tregs in PBL of transplanted patients. Indeed, kidney transplant patients on rapamycin as a maintenance therapy at 1 year post-transplantation had significantly higher fractions of Tregs in PBL compared to patients on calcineurin inhibitors (CNI) 1.
conversion from CNI to rapamycin or to mycophenolate mofetil (MMF) increased the numbers and fraction of Tregs in PBL 2.
CD28 co-stimulation blockade using belatacept or CNI reduces IL-2 levels and adversely affects Tregs. Low-dose IL-2 might be combined with these immunosuppressive drugs to counteract this deleterious effect on Tregs, as previously demonstrated 3.
Reference
1 Segundo DS, Ruiz JC, Izquierdo M, et al. Calcineurin inhibitors, but not rapamycin, reduce percentages of CD4+CD25+FOXP3+ regulatory T cells in renal transplant recipients. Transplantation 2006; 82: 550– 557.
2 Gallon L, Traitanon O, Sustento-Reodica N, et al. Cellular and molecular immune profiles in renal transplant recipients after conversion from tacrolimus to sirolimus. Kidney Int 2015; 87: 828–838.
3 Zeiser R, Nguyen VH, Beilhack A, et al. Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood 2006; 108: 390–399.
1- Natural Treg cells express CD25 and has special transcription factor Fox3p which is responsible for their activation toward immune tolerance.
2- Tr1 regulatory cells which is cytokine synthesis producing factor as it secrete IL-10 which inhibit inflammatory cytokine production and modulate APCs and act toward immune tolerance. It also secrete TGF-β which add to immune tolerance.
3- Th3 regulatory cells it induce immune suppression following ingestion of an antigen ( oral immune tolerance). It secrete TGF-β and help in IgA secretion.
4- CD8 regulatory cells
5- NK regulatory cells recognize antigens that express CD1d molecule.
ATG deplete absolute lymphocytic count , but affect T cell conventional count more than Treg count, Treg also can be renewed faster than conventional count.
AntiCD25 monoclonal antibodies like basiliximab and dacluzimab they affects Treg uncertainly, they affect modulation of CD25 expression on Treg without affecting number but this effect is transient.
Anti CD52 monoclonal antibody alemtuzumab…CAMPATH-1H help immune tolerance as it deplete conventional T cells more than Treg so the number of Treg increase relative to conventional T cells , also increase anti-inflammatory cytokines like IL-10, IL-4, TGF-β, and decrease inflammatory cytokines as IL-17 and INF gamma. CNI cyclosporine and tacrolimus affect negatively on Treg as they decrease Fox3p expression , and decrease IL-2 which is regulator of Treg proliferation. MMF help in Treg homeostasis and function, it increase Treg over Th17. Steroid therapy methylprednisolone alters T cell composition to favorable Treg cells , also can facilitate Fox3p expression and TGF-β signaling. mTor inhibitors increase Treg cells proliferation in comparison to cyclosporine, unfortunately, this has no change of graft loss, neoplasm development and rejection episodes. CTLA4-Ig as balatacept and abatacept both inhibit CD28 co-stimulation, which decrease effector T cells and promote Treg homeostasis. Rituximab deplete B cell population , it is unclear now to determine its effect on Treg cells through increase CD4 CD25 Treg population , some studies said it increase Treg and some studies showed no effect. Akiko Furukawa, Steven A. Wisel, Qizhi Tang. Impact of immune-modulatory drugs on Treg. Transplantation. 2016 Nov; 100(11): 2288–2300. Maryam Gol-Ara, Farhad Jadidi-Niaragh, Reza Sadria,Gholamreza Azizi, and Abbas Mirshafiey. The Role of Different Subsets of Regulatory T Cells in Immunopathogenesis of Rheumatoid Arthritis. Hindawi. Volume 2012.
Regulatory T cell (TREG): these cells are the major regulators of theimmune response. They can be distinguished from other T cells by theexpression of high levels of CD25 and the transcription factor FOXP3.“Natural” TREG comes directly from the thymus, and helps maintain self-tolerance. They are subpopulations of T lymphocytes defined by the expression of CD4+ and CD25+ molecules, as well as by the transcription factor FOXP3. Treg cells exhibit high expression of the IL-2α receptor (CD25) and low expression of CD127. With the use of Treg cells in the therapy of human diseases, it is important to distinguish between cell subtypes. Expression in the Helios molecule can be effective in differentiating between the subtypes of tTreg and iTreg/pTreg. Helios is expressed in the thymus, so it may be a marker to identify tTreg from the other populations of Treg, and it acts as upregulation in FOXP3 protein. Cells have super-expression of Helios has a superior effect of peripheral immunosuppression.
Treg-cell therapyThe concept of cellular immunotherapy with Treg is to give the patient Treg cells to decrease the exaggerated immune response in organ transplants. In vivo, low-dose IL-2 treatment increases Treg expansion and is used in the treatment of graft versus host disease (GVHD) and hepatitis C virus-induced cryoglobulinemic vasculitis and, together with rapamycin. Some authors suggest the use of rapamycin for Treg expansion in vivo with an approximately 75–80% yield of pure cells and total depletion of CD8 and CD19. Three categories of GMP-grade clinical Treg can define: first generation (CD4+CD25+); second generation, bone fide Treg (CD4+CD25+CD127low/−) and third generation naive Treg (CD4+CD25+CD127low/−CD45Ra+). These three types of Treg can be isolated and expanded by Il-2.
Reference:
Cadiele Oliana Reichert, Joel da Cunha, Débora Levy, Luciana Morganti Ferreira Maselli, Sérgio Paulo Bydlowski and Celso Spada (July 12th 2017). Regulatory T Lymphocytes (Treg): Modulation and Clinical Application, Lymphocyte Updates – Cancer, Autoimmunity and Infection, Gheorghita Isvoranu, IntechOpen, DOI: 10.5772/intechopen.69152. Available from: https://www.intechopen.com/chapters/55657
Do you think that all subtypes of Treg have the same potential in induction of tolerance (you have to classify the Treg first)
Five subsets of Tregs had been identified:
nTregs ( natural), iTregs ( peripheral), Tr1 cells, CD8+ Tregs, IL-17-producing FOXP3+ Tregs. Each of them seems to play different role in controlling immune system. Naturally occurring Tregs express their suppressive effect through cell contact by membrane bound molecules, while Tr1 is contact dependent and is based mainly on cytokines such as IL-10, TGF-beta.
References:
Zhang H., Kong H., Zeng X., Guo L., et al. Subsets of regulatory T cells and their roles in allergy. . Journal of Translational Medicine 2014, 12:125
Jonuleit H., Schmitt E.The Regulatory T Cell Family: Distinct Subsets and their Interrelations. J Immunol 2003; 171:6323-6327.
What are the immunosuppressive medications that potentiate the tolerance function of Treg?
steroids, mTORi, MMF, efalizumab( Anti LFA-1i), Tocilizumab ( Anti IL-6 ab), Anti CD28 ab, TNFi, CTLA4 Ig.
Reference:
Furukawa A.,Wisel S.A., Tang Q. Impact of immune-modulatory drugs on Treg. Transplantation. 2016 November ; 100(11): 2288–2300.
There are several types of T reg as CD4+ T reg expressing FOXP3, CD8+ T reg cells , and IL 10 producing T reg cells type 1.
The major role of T reg cells in tolerance is played by CD4+ T reg cells expressing FOXP3,CD25, and alpha chain of IL2 receptor.
The effect of immunosuppressive drugs on T cells is through the balance between suppression of effector T cells and activation of T reg cells. Some immunosuppressive drugs are friendly with T reg cells such as ATG, anti CD52, MMF and mTOR.
Sub types of Treg cells: Natural Treg cells, induced Treg cells, memory Treg cell, and other sub types of Treg cells that are illustrated in attached figure. Activated memory Tregs arise from thymic-derived natural Tregs or peripherally induced Tregs. A functional specialization of Tregs has been described. Tregs can express distinct transcription factors, chemokine receptor to specifically inhibit TH1, TH2, TH17, or TFH responses.
An increase in circulating HLA-DR+ mTregs is associated with better outcome in stable recipients.
Some studies have demonstrated enhancement of Treg function using clinically relevant doses of CNIs.
Inhibitors of the mTOR pathway are well-established pro-Treg factors, and can increase and stabilize Treg phenotype
T reg are subdivided according to expression of CD25,FOXP3 and CD45RA in to 3 populations 1 1- Population 1:naïve Treg FOXP3+CD45RA+CD25++ 2- Population 11:effecr T reg FOXP3hiCD45RA–CD25+++,, most suppressive one ,derived from 1,short life span 3- Population 111:memory Treg FOXP3+CD45RA–CD25++,no information about its role
They can be divided according to the origin to2
1- nTREG (natural)cells from thymus
2- iTREG(induced regulatory) cells, peripherally generated from t effector cells
They can be divided according to the level of FOXP3 expression and the isoform of CD45 ,2
1- Resting CD45ra+FoXP3low;
2- 2- CD45ra–FoXP3high
3- the CD45ro+FoXP3low: is not suppressant. It had effector activity since they produce cytokines
The resting can get CD45ra–FoXP3 high phenotype once activated and both of them are suppressive
1- Edozie, Francis C.1,2; Nova-Lamperti, Estefania A.1,2; Povoleri, Giovanni A.M.1,2; Scottà, Cristiano1,2; John, Susan2,3; Lombardi, Giovanna1,2; Afzali, Behdad1,2,4 Regulatory T-Cell Therapy in the Induction of Transplant Tolerance, Transplantation: August 27, 2014 – Volume 98 – Issue 4 – p 370-379 doi: 10.1097/TP.0000000000000243. 2- Li XC, Turka LA. An update on regulatory T cells in transplant tolerance and rejection. Nat Rev Nephrol. 2010 Oct;6(10):577-83. doi: 10.1038/nrneph.2010.101. Epub 2010 Aug 3. PMID: 20683480.
Treg help to maintain graft tolerance and graft acceptance Tregare CD4+cells that Express high level of IL-2 receptor CD25 along with transcription factor FOXP3.main 2 types of Treg are Treg natural that derived from thymus and peripheral inducible which are induced either from natural Treg or naiveCD4+CD25- cells ,main idea of using Treg in tolerance is how to expand their number either endogenous or by infusion exogenously.
Alot of immunosuppressant used to increase Treg activation and maintenance like ATG ,anti IL-2 receptors Ab and anti CD52 Ab all potentiate Treg expansion also mTOR inhibitors promote Treg survival and function .
The regulatory T cells , formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens,andprevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells.Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Recent research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.
Four sub types :-
natural Treg( nTreg),
inducible Treg( iTreg),
IL-10 producing type I( TrI, CD8).
IL-17 producing Treg.
Medications , ?
steroids,mmf
, mTORi,
Tocilizumab ( Anti IL-6 ab),
Anti CD28 ab,
Ahmed Ziada
3 years ago
T cell is the main player in transplant immunology it is responsible for acute cell mediated rejection through direct pathway of recognition of transplanted HLA by recipient T cells
APCs present foreign peptides to recipient cytotoxic CD8 leading to the cell activation
T cell also responsible for chronic graft damage through indirect pathway in which donor cells engulf it by recipient APCS & presented to recipient CD for and helper t cell
T cell also release cytokines which activities B cells and antibody Mediated rejection
Ahmed Omran
3 years ago
T reg cells inhibit potentially harmful effects of Th cells, through inhibiting cell proliferation ,cytokine production thus preventing autoimmunity and suppressing allo immune responses.
Naturally occurring T reg produce their effect through cell contact by membrane bounding molecules but Tr 1 effect is related to IL-10.
T reg effects are enhanced by steroids ,mTor i ,MMF ,eflizumab and toclizumab.
References;
Handbook of Kidney Transplantation ,Danovitch,G, Sixth edition
Furnkaw,A,et al : Impact of immune modulating drugs on Treg,Transplantation,2016,Nov,100(11):2288-2300
Wael Hassan
3 years ago
t cells responsible for innate immunity (cellular immunity)and also activation of b cells that produce plasma cells and then immunoglobulins so T cells responsible for both cellular and humoral immunity
Mohamed Essmat
3 years ago
CD8 T cells: Recognize antigenic peptides presented on MHC class I They have direct cytotoxicity to target cells they can secrete cytokines CD4 T cells: Recognize antigenic peptides presented by MHC class II molecules presented by APC . They play a role in cellular rejection and antibody mediated rejection, provide help to CD8+ T cells so help graft directed cell response as well as having an important role in HLA specific antibody formation via B cell activation and IgM to IgG isotype switching. Memory T cells: They may be present due to prior allogenic exposure ,they can be activated without co-stimulation. T regulatory cells: Treg suppress the function of different cells as CD4+, CD8+ T cells, macrophages, dendritic cells, NK cells & B cells . They include subclass natural treg,tr1,th3,Cd8treg and NKreg which plays important role in tolerance and used as cellular immune therapy.
Abdullah Raoof
3 years ago
The ability of the immune system to differentiate self from nonself is critical in determining the immune response to antigens expressed on transplanted tissue. Even with conventional immunosuppression, acceptance of the allograft is an active process often determined by the presence of regulatory T cells (Tregs). Tregs classically are CD4+ cells that constitutively express high levels of the IL-2 receptor α chain CD25, along with the transcription factor Foxp3. The use of Tregs in the field of solid organ transplantation is related specifically to the objective of achieving tolerance, with the goal of reducing or eliminating immunosuppressive drugs as well as maintaining tissue repair and managing acute rejection. A key issue in clinical use of Tregs is how to effectively expand the number of Tregs, either through increasing numbers of endogenous Tregs or by the direct infusion of exogenously expanded Tregs. In order to realize the benefits of Treg therapy in solid organ transplantation, a number of outstanding challenges need to be overcome, including assuring an effective expansion of Tregs, improving long-term Treg stability and reduction of risk-related to off-target, nonspecific, immunosuppressive effects related specially to cancer.
AMAL Anan
3 years ago
***Transplant tolerance has been defined as maintenance of stable allograft function in the absence of immunosup- pressive therapy
The role of regulatory T cells (Treg) in the generation and maintenance of immune tolerance is an attractive yet elusive one
Tregs are defined as those anergic and hyporesponsive to stimulation of T-cell receptor (TCR) with suppressive action on the proliferation and activation of helper CD4+ T cells and cytotoxic CD8+ T cells via cell-to-cell contact. Tregs with their Foxp3-expressing marker are strongly suppressive of proliferation of effector T cells and memory T cells, thus controlling excess immune response to foreign antigens, and maintain self-tolerance.
***Two major subsets of Tregs have been defined based on their developmental origin: (1) thymus-derived natural Tregs (nTregs), characterized by constitutive Foxp3 expression, and (2) peripheral induced Tregs (iTregs), where Foxp3 expression seems unstable [14]. Although both T-cell subsets possess regulatory properties, they differ in their developmental pathways, TCR repertoires, and activation requirements. nTregs develop within the thymic medulla, around Hassall’s corpuscles, under the effect of both IL-2 and transforming growth factor (TGF)-β . The other crucial step for Treg development is the engagement of TCRs with MHCII molecules loaded with self-peptides. After exiting the thymus, nTregs form 5–10% of the total peripheral T cells. Their presence in the periphery as a stable population of T cells
Tregs for Transplant Tolerance contributes to the maintenance of peripheral tolerance and prevents the development of autoimmunity .In contrast, iTregs develop in the periphery under the influ- ence of different cytokines as an adaptive immune response. A milieu rich in IL-2 and TGF-β appears to polar- ize the naïve T cells towards iTregs . This makes iTregs display more flexible biomarker features with the capacity to transform into different T-cell subtypes depending on the prevailing cytokine milieu . Clinical trials have shown that iTregs generated in vitro are com- parable to nTregs in immunoregulatory activity. How- ever, withdrawal of the TGF-β from iTreg cultures will result in rapid loss of Foxp3 expression, along with a re- version to a cell phenotype akin to conventional CD4+ T cells [18]. In stark contrast, Foxp3 expression by nTregs is independent of TGF-β, as evidenced by the normal amount and function of nTregs in TGF-β-deficient mice.
***Tregs have been used experimentally to explore treatment of other auto- immune disease conditions, such as colitis, lupus, diabetes mellitus, and glomerulonephritis. The first proof-of- concept clinical trial of polyclonal adaptive Treg transfer to treat graft-versus-host disease turned out to be promising . A major limitation of polyclonal Tregs is the low abundance of the specific clones of interest within the polyclonal repertoire. While antigen-specific Tregs would be superior, their isolation and expansion are still chal- lenging. Recently, Trivedi et al. conducted a clinical trial on a group of live-donor renal transplantation patients using pretransplant stem cell transplantation. The Tregs for Transplant Tolerance patients achieved successful withdrawal of the immunosuppressants with low-dose daily steroid monotherapy. They concluded that generation of peripheral Tregs was necessary to maintain tolerance and that the survival and presence of Tregs is important to protect the graft from chronic rejection.
References:
1-Halloran PF: Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004; 351:2715–2729. Kidney Dis 2018;4:205–213 DOI: 10.1159/000490703
2-Scandling JD, Busque S, Shizuru JA, Engle- man EG, Strober S: Induced immune toler- ance for kidney transplantation. N Engl J Med 2011;365:1359–1360.
3-Starzl TE: Immunosuppressive therapy and tolerance of organ allografts. N Engl J Med 2008;358:407–411.
4-Roussey-Kesler G, Giral M, Moreau A, Subra JF, Legendre C, Noël C, et al: Clinical opera- tional tolerance after kidney transplantation. Am J Transplant 2006;6:736–746.
AMAL Anan
3 years ago
* Immunosuppressive potentiate the tolerance function of Treg?
steroids, mTORi, MMF, efalizumab( Anti LFA-1i), Tocilizumab ( Anti IL-6 ab), Anti CD28 ab, TNFi, CTLA4 Ig.
AMAL Anan
3 years ago
The regulatory T cells , formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are
immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells.Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Recent research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.
Subtypes of TREG :
1-nTregs :
The CD4(+)CD25(+)Foxp3(+) cells, which secret IL-10 and TGF-β, and represent one of the largest subsets of Treg.
2- iTregs :
In contrast to nTregs, iTregs are peripherally induced Tregs. Naive CD4+ T cells in the periphery are induced to express Foxp3 in response to foreign antigens [9] and these cells have suppressive function similar to nTregs [16]. iTregs has considerable significance in preventing asthma if generated early enough in life [4]. In addition, Th3 cells that secrete TGF-β and IL-10 belong to this subset .
3-Tr1 cells :
The CD4+ T cells that do not express Foxp3, but secret IL-10 and suppress effector functions of Th cells are known as Tr1 cells.
4- CD8 + Tregs :
A subset of Tregs expressing CD8 is rapidly generated from OT-1 CD8 cells in the presence of IL-4 and IL-12, produce IL-10, and exhibits a unique cell-surface phenotype with coexpression of activation and naive cell-associated markers. They are also observed in tonsils, but rarely detected in peripheral blood. IL-17-producing Foxp3+ Tregs.
It is reported that human peripheral blood and lymphoid tissue, but not thymus contain a significant number of CD4(+)Foxp3(+) T cells that express CCR6 and have the capacity to produce IL-17 upon activation. These cells coexpress Foxp3 and RORgammat transcription factors. The CCR6(+)IL-17-producing Foxp3+ Tregs strongly inhibit the proliferation of CD4(+) responder T cells. Human CCR6(+) IL-17-producing Foxp3+ Tregs are differentiated from the CD4(+)Foxp3(+)CCR6(-) Tregs upon T-cell receptor stimulation in the presence of IL-1beta, IL-2, IL-21, IL-23, and human serum
References:
1- Warner JO, Kaliner MA, Crisci CD, Del Giacco S, Frew AJ, Liu GH, Maspero J, Moon HB, Nakagawa T, Potter PC, Rosenwasser LJ, Singh AB, Valovirta E, Van Cauwenberge P. World Allergy Organization Specialty and Training Council. Allergy practice worldwide: a report by the World Allergy Organization Specialty and Training Council. Int Arch Allergy Immunol. 2006;139(2):166–174. doi: 10.1159/000090502.
2-Barnes PJ. Pathophysiology of allergic inflammation. Immunol Rev. 2011;242(1):31–50. doi: 10.1111/j.1600-065X.2011.01020.x.
3/ Afzali B, Lombardi G, Lechler RI, Lord GM. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol. 2007;148(1):32–46. doi: 10.1111/j.1365-2249.2007.03356.x.
Last edited 3 years ago by AMAL Anan
Jamila Elamouri
3 years ago
1- Naturally occurring CD4+CD25+ Tregs developed from CD4+T cell precursors directly, under the influence of medium avidity interactions with thymic epithelial cells. o the conventional CD4+CD25-T cells express FoxP3, which conferred suppressor function of the T cell subset. o Activated T cells express CD25, GITR, OX40, L-selectin, CTLA-4 ( all these markers are useful for phenotyping identification of naturally occurring CD4+CD25+
2- Induced Tregs develop from naïve conventional CD4+T cells by either: o Cell contact-dependent interaction with naturally occurring CD4+CD25+ Tregs. o Under the influence of suppressive agents like IL-10, TGF-B, vit D3, Dexamethasone and other inhibitory mechanisms. Reference:
1. Jonuleit H, Schmitt E. The Regulatory T Cell Family: Distinct Subsets and their Interrelations. J Immunol [Internet]. 2003 Dec 15;171(12):6323 LP – 6327. Available from: http://www.jimmunol.org/content/171/12/6323.abstract
Ahmed mehlis
3 years ago
Transplantation is unusual in that T cells can recognize alloantigen by at least two distinct pathways: as intact MHC alloantigen on the surface of donor cells via the direct pathway; and as self-restricted processed alloantigen via the indirect pathway. Direct pathway responses are viewed as strong but short-lived and hence responsible for acute rejection, whereas indirect pathway responses are typically thought to be much longer lasting and mediate the progression of chronic rejection. However, this is based on surprisingly scant experimental evidence, and the recent demonstration that MHC alloantigen can be re-presented intact on recipient dendritic cells—the semi-direct pathway—suggests that the conventional view may be an oversimplification.
●Direct pathway :
CD4 T cell responses are limited to the first few weeks after transplantation
“direct” pathway activation is largely due to recognition of intact alloantigen acquired onto the surface of host APCs by transfer of donor-derived extracellular vesicles.
●in direct pathway .
CD4 T cell responses against self-restricted processed alloantigen can last much longer than those against intact alloantigen. functional role for the indirect pathway CD4 T cell response in the progression of chronic allograft
● semi direct pathway.
semi-direct allorecognition is a means by which recipient T cells may recognize “intact” alloantigen. This will result in activation of the same T cell clones as would respond via direct pathway allorecognition. In contrast, those T cell clones responding to the processed alloantigen via the indirect pathway are likely to be very different.
●Reference :
. Lakkis FG, Li XC. Innate allorecognition by monocytic cells and its role in graft rejection. Am J Transplant. (2017) 18:289–92. doi: 10.1111/ajt.14436
PubMed Abstract | CrossRef Full Text | Google Scholar
2. Oberbarnscheidt MH, Zeng Q, Li Q, Dai H, Williams AL, Shlomchik WD, et al. Non-self recognition by monocytes initiates allograft rejection. J Clin Invest. (2014) 124:3579–89. doi: 10.1172/JCI74370
PubMed Abstract | CrossRef Full Text | Google Scholar
Mohammed Sobair
3 years ago
T cells become activated through:
Direct pathway:
interaction of their T cell receptors with intact allogeneic MHC molecules on donor cells
and/or donor.
Indirect pathway:
MHC peptides presented by self-MHC molecules on recipient antigen-presenting cells
(APCs) .
Semi-direct pathway:
In addition, recent studies show that alloreactive T cells can also be stimulated through
recognition of allogeneic MHC molecules displayed on recipient APCs (MHC cross-
dressing) after their transfer via cell–cell contact or through extracellular vesicles(1).
T Cell Allorecognition and Rejection of Vascularized Solid Organ Transplants:
Early acute rejection of kidney allografts is essentially initiated by CD4+ T cells
recognizing donor MHC class II molecules in a direct fashion.
This is associated with a rapid trafficking of graft DCs to the host spleen presumably
occurring via reverse trans endothelial vascular migration .
, some studies suggest that these allografts could be rapidly infiltrated with recipient
endogenous alloreactive effector memory T cells.
these memory T cells account for resistance to allograft tolerance induction .
Therefore, primarily naïve and presumably endogenous memory T cells activated in a
direct fashion mediate early acute rejection of solid organ transplants.
Suppression of this response by calcineurin inhibitors and other immunosuppressive
agents is regularly achieved in transplanted patients, thereby allowing large-scale
There is strong circumstantial evidence suggesting that T cells activated indirectly are
Lymphocytes and Allograft Rejection. Immunol.14 December 2016
Theepa Mariamutu
3 years ago
Impact of approved immunosuppressive drugs on Treg
Anti-thymocyte globulin
• rATG is a polyclonal preparation from rabbits immunized with human thymocytes that depletes CD4+ and CD8+ T cells with CD8+ T cells recovering more rapidly and completely than CD4+ T cells.
• ATG mediated immunosuppression induces apoptosis and induction of T-cell anergy at low doses, antibody-dependent cellular cytotoxicity at moderate doses, and complement-mediated lymphocyte lysis at high doses
• Treatment of human peripheral blood lymphocytes with low-dose ATG induces expression of CD25 and FOXP3 in CD4+CD25− cells
• ATG induction therapy reduces the absolute number of Treg, but less than that for Tconvs, altering the Treg/Tconv ratio.
• Treg recover faster during immune reconstitution following ATG treatment, contributing to the sustained elevation of Treg/Tconv ratio
• High-dose ATG impairs thymic generation of Tconv and Treg cells in allogeneic hematopoietic stem cell transplantation
• ATG therapy regulate antigen-specific immune responses by inducing memory-like Treg and T cells such as Th2 and IL-10-producing Tr1 cells.
• ATG is not only induces T cell depletion, but also in relative preservation of Treg especially at lower doses.
Anti-CD25 mAb
• basiliximab and daclizumab- block the IL-2-binding site of CD25
• suppress immune response by targeting recently activated effector T cells that express CD25
• inhibit activation of CD25− T cells by blocking CD25+ DCS from transpresentation of IL-2
• In transplant patients, Basiliximab can lead to a transient reduction of both Treg and down-modulation of CD25 expression on Treg without deleting the cells or impairing their functions
• CD25lo Treg are able to increase CD127 expression and IL-7 responsiveness following daclizumab treatment in MS patients that explains Treg rescue in the absence of IL-2 signaling
• Daclizumab able to increase CD56hi NK cells by increasing the bioavailability of IL-2. CD56hi NK cells suppress immune responses by killing autologous activated T cells or allogeneic APCs
• anti-CD25 inhibits effector T cells and effect on Treg appears to be trasient
• Anti-CD25 mAb may promote Treg-independent tolerogenic mechanisms that may offset anti-CD25 mAb impairment of Treg.
Anti-CD52 mAb
• CD52 is highly expressed on T cells and B cells
• ADCC and complement activation via anti-CD52 are likely mechanisms for alemtuzumab-mediated killing of CD52+ cells
• Depletes activated Tconvs over Treg, resulting in a transient elevation of the Treg to Tconv ratio
• induce conversion of Tconv into Treg, increase anti- inflammatory cytokines IL-4, IL-10 and TGF-β, and suppress proinflammatory cytokines IFN-γ and IL-17
CNI
• inhibit the intracellular phosphatase calcineurin, which dephosphorylates cytosolic nuclear factor of activated T cells (NFAT) to allow for its nuclear translocation and transcriptional activation of cytokine genes such as IL-2
• IL-2 is a regulator of proliferation, survival, and maturation for all T cell subtypes, including Treg
• impair Treg by directly inhibiting Treg activation, inhibiting the generation of pTreg, and indirectly by limiting IL-2 production by Tconvs
• NFAT binding to the CNS1 enhancer is important to pTreg induction88 and its binding to CNS2 enhancer is critical for Treg stability
• High-dose CNI exposure alters gene expression in Treg
• Treg are resistant to low-dose CNI and combing CNIs with sirolimus restore Treg suggest that reducing CNI dose may not only spare patients from the nephrotoxicity, but also spare Treg
Mycophenolate
• promotes Treg predominance over Th17 cells by inhibiting T cell Ig mucin-1 expression, a protein that promote differentiation into effector T cells than Treg
• But administration of supra-therapeutic MMF monotherapy to mice receiving Treg cell therapy reduced the efficacy of Treg
• In liver transplant recipients, conversion from CNI to MMF with a 1-time dose of daclizumab showed an increase in the percentage of Treg from baseline
• Analysis of kidney transplant patients on stable immunosuppression regimens identified higher levels of CD4+CD25highFOXP3+ Treg in patients receiving MMF versus everolimus
mTOR Inhibitors
• acts through mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2)
• Th1 and Th17 differentiation of CD4+ T cells are dependent on mTORC1
• Th2 differentiation requires mTORC2
• In kidney transplant recipients, patients on sirolimus maintenance immunosuppression show a 4-fold increase in circulating Treg when compared to patients receiving cyclosporine
• targeting mTOR may promote pTreg induction and selectively suppress Tconvs while sparing Treg. Treg favoring effect is dose-dependent and high doses of mTOR inhibitors will also negatively impact Treg function
References
Furukawa, A., Wisel, S. and Tang, Q., 2016. Impact of Immune-Modulatory Drugs on Regulatory T Cell. Transplantation, 100(11), pp.2288-2300.
Dalia Ali
3 years ago
T cells are required for allograft rejection. Alloreactive T cells can be found in the naïve and memory T cell populations, but both require recognition of nonself MHC molecules to become activated. Reactions mediated by naïve T cells take longer to develop than those mediated by memory T cells, which can be generated more quickly and with higher numbers of cells (secondary response). During allograft rejection, both populations are activated simultaneously.
CD4 and CD8 Coreceptors T cells fall into two major classes with different effector functions, distinguished by the expression of the cell-surface proteins CD4 and CD8 .
Both CD4 and CD8 have a cytoplasmic tail that can associate with signaling proteins important in T cell activation. CD4 and CD8 binding to MHC are required to make an effective response. Thus these molecules are called coreceptors.
These processes are controlled by cytokines, including IL-2, which acts on the T cell in an autocrine fashion or by paracrine secretion to neighboring T cells. Activated T cells produce the alpha subunit (CD25) of the IL-2 receptor (IL-2R), enabling a fully functional signaling receptor composed of α, β, and γ subunits that can bind IL-2 with high affinity, which in turn initiates another pathway mediated in part through the protein mammalian target of rapamycin (mTOR).
CD4 and CD8 T cells have different roles during immune responses.
CD4 T cells are both effectors and regulators and have heavy cytokine secretion. After prolonged stimulation, CD4 T cells tend to express groups (signatures) of several cytokines, probably depending on the local environment, nature of the antigen, and type and activation status of the APC.
Feehally J. Comprehensive Clinical Nephrology. SIXTH EDITION.2019
Nasrin Esfandiar
3 years ago
There a two subtypes of Tregs:
1- natural Treg (nTreg)are CD4+ CD25+ Foxp3+
2- induced Treg (iTreg) is developed by tolerance
Tregs secret cytokines including TGFβ, IL-10 and IL-35. Tr1 regulatory T cells secret IL-10 and have suppressor function.
Drugs such as mTOR inhibitors potentiate tolerance function of T regulatory. But CNIs have opposite effect on Treg.
Nasrin Esfandiar
3 years ago
T cells have important role in acute and chronic rejection .Effector T cells cause graft damage after recognition of allo-Ags by CD4+ and CD8+ T cells .So first step is allo-recognition which is induced by major or minor histocompatibility complex or antigens (MHC and miH). Ags can be recognized by direct, indirect and semi-direct pathways to recipient TCRs. Some Chemokines and cytokines trigger recruitment of recipient T cells into the graft. Both naive and memory T cells can initiate an immune response. Memory cells have rapid response to prior Ags and are resistant to apoptosis .This kind of rejection is not responding to treatment very good. CD8+ T cells are contributing in rejection, too. They contain perforin, granzyme A and Fas ligand and perform their action by cell killing.
Activation of Tcells is based on three signals. Binding of HLA introducing antigen to Tcell receptor makes signal 1. Signal 2 is co-stimulation through integrins, B7-CD28, CD40-CD154 and other co-stimulatory molecules and signal 3 is made by cytokine roles in proliferation and differentiation of Tcells to effector T lymphocytes.
Ben Lomatayo
3 years ago
Question 1;
Thymus-derived regulatory T(tTreg)
Peripherally-derived regulatory T(pTreg)
In Vitro-induced T(iTreg)
Depending on whether the cells stably express FOXP3 ; pTreg and iTreg cells are divided into ;
Classical CD4 +ve FOXP3 Treg cells
CD4 +ve FOXP3 type 1 regulatory T( Tr1) cells ; Their immunomodulatory making them very important target for prevention of organ rejection
Question 2 ;
mTORi e.g. Sirolimus or Everolimus are associated with up regulations of Treg and therefore augment the tolerance function of Treg.
Ben Lomatayo
3 years ago
T cells are important part of adaptive immunity and it plays key roles in allorecognition, signal transduction. T Cells includes ; CD4,CD8, Regulatory cells, and Memory cells.
T cells interact with B cells, and Macrophages of innate immunity.
Reference ; Oxford hand book of nephrology & hypertension, second edition
Asmaa Khudhur
3 years ago
TCRs expressed on T lymphocytes membrane
TCRs recognize alloantigens via two pathways
direct and indirect
T lymphocytes activation and prolifereration and differentiation depends on APCs
T lymphocytes activation depend on 3 signals :
Signal 1 /TCR signaling
Signal 2/Co-stimulation
Signal 3/ Cytokines
Types of T lymphocytes :
Cytotoxic T cell
T-helper cells
T regulatory cells
Memory cells
T-lymphocytes subsets :
Th1 lymphocytes
Th2 lymphocytes
Th17 lymphocytes
Tfh lymphocytes
Cytotoxic T lymphocytes
The IS that act on T lymphocytes are :
Steroid
MMF
CNIs
MTOR
Ameluzumab
Reference is Handbook of kidney transplantation by Danovitch
Ramy Elshahat
3 years ago
What is the role played by T cells in transplant immunology?
There is two main types of Tcells Cd4(helper) which interact with antigen presented by APC on HLA class 2
Cd8(cytotoxic) which interact with antigen presented on HLA class 1
Lymphocytes are mainly in inactive(Naive) state and active lymphocytes usually not exceed 0.1% but in kidney Transplantation this figure become 2-10%
Naive Cd4Tcell needs antigen recognition to be activated (adaptive) by 3 main pathways
Direct: by donor APC (100folds potent)
indirect:by antigenic part presented by recipient APC
Semidirect: by whole donor HLA presented by recipient APC
After Cd4Tcell recognition it’s activation started by 3signals
Signal 1: connection between TCR Cd4 and antigen presented on APC
signal 2: connection between cd80/86 on APC and Cd28 on t cell
Signal 3: Cd4Tcell proliferation under effect of IL 2on Cd25 and differentiate into effector t cells which includes
Th1: secrets IL2 and interferone gamma and other inflammatory cytokines and aggravated immune system
Th2: secrets IL10 and antiinflammatories cytokines and inhibit immune response
Th17: secrets IL17 and aggravates immune response
Tfh: which introduce antigen to bcell in the 2ry lymphoid organs and starts humoral immune response
Tmemory: which life longer and get activated without signal 2 and resistant to treatment.
Treg: which also includes subclass natural treg,tr1,th3,Cd8treg and NKreg which plays important role in tolerance and used as cellular immune therapy
Also treg affected by immunosuppressant medications as below
Cni decrease number and function of Treg by inhibition of IL2 secretion
ATG depleting both conventional and treg but treg regenerate faster
Alemutzumab affect conventional tcell more than treg and elicit more tolerance.
MTOR,MMF and steroids increase treg expression and activity.
Heba Wagdy
3 years ago
Allorecognition and activation of alloreactive T lymphocytes depend on three pathways,
direct: T cells react directly to antigens presented by donor antigen presenting cells, this response is associated with acute rejection.
indirect pathway: T cells recognize self antigen presenting cells presenting peptides originating from donor MHC antigens
semidirect immune response: intact allogenic HLA/peptide complex transferred from donor cells to recipient cells activate T cells (1)
CD4+ T cells:
recognize antigenic peptides presented by MHC class II molecules presented by APC as dendritic cells, B cells and macrophages.
they can differentiate into other effector cells. (2)
CD8+ T cells:
recognize antigenic peptides presented on MHC class I which present on most cells
exert direct cytotoxicity to target cells
have proinflammatory function as can secrete cytokines (3)
memory T cells:
they may be present due to prior exposure to alloantigen
memory cells can survive in absence of antigens and can be activated without costimulatory molecules
resistant to apoptosis. (4) T regulatory cells:
Treg suppress the function of different cells as CD4+, CD8+ T cells, macrophages, dendritic cells, NK cells & B cells through contact & non contact dependent mechanisms. (5)
T helper cells:
T helper cells play a role in cellular rejection and antibody mediated rejection, they provide help to CD8+ T cells so help graft directed CD8+ T cell response.(6)
CD4 T helper cells have an important role in HLA specific antibody formation via B cell activation and IgM to IgG isotype switching. (7)
(1) Issa, F., Schiopu, A. and Wood, K.J., 2010. Role of T cells in graft rejection and transplantation tolerance. Expert review of clinical immunology, 6(1), pp.155-169.
(2) DuPage, M. & Bluestone, J. A. Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease. Nat. Rev. Immunol. 16, 149–163 (2016)
(3) Mittrücker, H. W., Visekruna, A. & Huber, M. Heterogeneity in the differentiation and function of CD8+ T cells. Arch. Immunol. Ther. Exp. 62, 449–458 (2014).
(4)Benichou, G., Gonzalez, B., Marino, J., Ayasoufi, K. and Valujskikh, A., 2017. Role of memory T cells in allograft rejection and tolerance. Frontiers in immunology, 8, p.170.
(5) Romano, M., Tung, S.L., Smyth, L.A. and Lombardi, G., 2017. Treg therapy in transplantation: a general overview. Transplant International, 30(8), pp.745-753.
(6) Marino J, Paster J, Benichou G. Allorecognition by T lymphocytes and allograft rejection. Front Immunol (2016) 7:582.
(7) Steele DJ, Laufer TM, Smiley ST, Ando Y, Grusby MJ, Glimcher LH, et al. Two levels of help for B cell alloantibody production. J Exp Med (1996) 183:699–703
Tahani Hadi
3 years ago
T cells are the major components of the immune system that derived from lymphoid progenitor cells then they become highly specialised each with different receptors which are produced by gene rearrangement making them specific to antigens by recognizing short peptide sequences of the Ag .
The specific receptors of T cells TCR give the total T cells ability to response to any Ag.
T cells are responsible of cell mediated immunity also they have effect against intracellular pathogens,tumors and non self cells.
Main types of T cells :
Cytotoxic T cells ;surface expression of CD 8 (CD 8+T cell) and can directly kill cells that express non self Ag .
Helper T cells; surface expression of CD 4 (CD4+T cell) help to activate macrophages and B cells by giving additional signals .
Regulatory T cells ; control the activity of other T cells and they are important and play role in graft tolerance.
Memory T cells; rapidly change to effector cells when re-exposure to Ag .
T cells activation controlled by 3 signals:
Signal 1 is necessary for T cells proliferation and differentiation but not sufficient alone and it’s produced by binding TCR to Ag (HLA peptides-APCs complex)this lead to their activation .
Signal 2 is mandatory for full T cell activation and differentiation to effector cells ,this occurs by co stimulatory receptors CD 28 on T cells with APCs.
Signal 3 achieved by cytokines named interleukin IL which are proteins secreted by APCs or T lymphocytes themselves such as IL -2.
Fatima AlTaher
3 years ago
When naïve T lymphocytes are activated after Ag presentation on APCs , they proliferate and differentiate into several effector cells 1- Cytotoxic T cells : they recognise their specific antigen when its presented on MHC Class I molecules
alloreactive T cells can recognize forign MHC Ags when presented by donor APCs followed by activation of CD4 helper or CD8 cytotoxic cells (direct allorecognition pathway)or Forign Ags are processed then present by recipient APCs to recipient CD4 helper T cells through MHC class II , followed by anhancing B lymphocytes activation , proliferation and Ab production with subsequent graft ingury .(1) 2- T-Helper Lymphocytes : they can differniate into several subtypes including Th1, Th2, Th17, TfH cells and regulatory T cells. T helper cells are activated in response to Ag presentation on MHC class II on APCs.
Functions : a- Each subtypes secretes a different panel of cytokines that can drive the immune response in a specific direction, so these CD4+T helper cells play a vital role in various immunologic processes as activation of cytotoxic T cells and APCs , maturation and differiation of B cells into plasma cells and memory B cells , antibody production by B cells, recruitment of various inflammatory cells PMNs, eosinophils and basophils as well as development of tolerance and suppression of immune responses
b- T reg are essential for identifying self from non self Ags, inducing natural tolerance through controlling alloreactive T cells , tissue repair and restrict cancer initiation .(2) 3- Memory T cells : they are either CD4+ or CD8+ and are important to provide immune system with memory against previously encountered antigens.
Ref
1- Callus, R., Buttigieg, J., Anastasi, A. A., & Halawa, A. (2017). Basic concepts in kidney transplant immunology. British journal of hospital medicine (London, England : 2005), 78(1), 32–37. https://doi.org/10.12968/hmed.2017.78.1.32 2- de Graav, G. N., Dieterich, M., Hesselink, D. A., Boer, K., Clahsen-van Groningen, M. C., Kraaijeveld, R., Litjens, N. H., Bouamar, R., Vanderlocht, J., Tilanus, M., Houba, I., Boonstra, A., Roelen, D. L., Claas, F. H., Betjes, M. G., Weimar, W., & Baan, C. C. (2015). Follicular T helper cells and humora
Abdulrahman Ishag
3 years ago
The role of T-cell in transplanation
T-cells are the centre of the adaptive immune response to transplant organs.
The role of T-cells in transplantation is allorecgnition, so they affect both rejection and tolerance .
T cells reacting directly to alloantigens presented by donor antigen-presenting cells (APCs) mediate the “direct” alloresponse ( acute rejection) .
The indirect alloresponse, in contrast, resembles more typical immune responses in which T cells recognize self-APCs presenting peptides on self-HLA molecules .
Cross-talk between B cells with immunoglobulin receptors that bind donor HLA molecules and internalize them ,resulting in focused presentation to indirectly alloreactive T cells that recognize peptide from the same allogenic HLA molecules and help antibody production by those B cells (chronic rejection) .
T-cells activation pass through 3 signal ;
1-TCR signaling
2-Co-stimulation
3- cytokines production
T-cells ( regulator) suppress the effector T cells with different antigen specificities and confer tolerance.
Regulatory T-cells are classified into;
-thymus derived Tregs (natural).
– peripheral inducible Tregs .
Inducible Tregs can be generated from natural Treg or naïve (CD4 ,CD25) cells upon T-cells receptor stimulation in the presence of cytokines such as TGF and IL-2 .
CD4 T-reg cells express high level of the IL-2 receptor alpha chain CD25,together with the transcription factor Fox3.
What are the immunosuppressive medications that potentiate the tolerance function of T-reg;
Calcinurin inhibitors decrease T-reg viability and proliferation.
The effects of mycophenolic acid on T-reg appear to be more variable .
Glucocorticoids appear not to affect T-regs.
mTOR inhibitors promote differentiation and expansion of T-reg as well as increase Foxp3expression,although their effect may decline over time .
induction therapy with thymoglobulin shifts the T-reg to T effector.
Basiliximab may have a deleterious effect on T-reg ,due to the high expression of CD25 on T-reg.
Alemtuzumab uses lead to the generation expansion of T-reg.
Because of the importance of the B7:CD28 interaction for maintenance and generation of T-reg ,the use of Co-stimulatory molecule blocker belatacept reduce their number.
There are none immunosuppressive drugs have been shown to increase T-reg population;
-Metformin
– Erythropoietin
Recent studies showed that inducible Treg treatment decrease serum DSA in a murine model ,indicating a potential use in treatment of humoral rejection.
Refferance; 1. Pietra BA, Wiseman A, Bolwerk A, Rizeq M, Gill
RG. CD4 T cell-mediated cardiac allograft rejection requires donor but not host MHC class II J Clin Invest. 2000;106(8):1003–1010. Steele DJ, et al. Two levels of help for B cell alloantibody production. J Exp Med 1996;183(2):699–703. Mohr Gregoriussen AM, Bohr HG: A novel model on DST-induced transplantation tolerance by the transfer of self-specific donor tTregs to a haplotype-matched organ recipient. Front Immunol 8: 9, 2017 Tang Q, Lee K: Regulatory T-cell therapy for transplantation: How many cells do we need? Curr Opin Organ Transplant 17: 349–354, 2012 Zwang NA, Leventhal JR: Cell therapy in kidney transplantation: Focuson regulatoryT cells. J Am SocNephrol28: 1960–1972, 2017 . Chen X, Oppenheim JJ, Winkler-Pickett RT, Ortaldo JR, Howard OM: Glucocorticoid amplifies IL-2-dependent expansion of functional FoxP3(1)CD4(1)CD25(1) T regulatory cells in vivo and enhances their capacity to suppress EAE. Eur J Immunol 36: 2139–2149, 2006
Gallon L,TraitanonO,YuY,ShiB,LeventhalJR,MillerJ,MasV,LX, Mathew JM: Differential effects of calcineurin and mammalian target of rapamycin inhibitors on alloreactive Th1, Th17, and regulatory T cells. Transplantation 99: 1774–1784, 2015
Kim KW, Chung BH, Kim BM, Cho ML, Yang CW: The effect of mammaliantargetofrapamycin inhibitiononThelpertype17 and regulatory T cell differentiation in vitro and in vivo in kidney transplant recipients. Immunology 144: 68–78, 2015
Bloom DD, Chang Z, Fechner JH,DarW, Polster SP, Pascual J, Turka LA, Knechtle SJ:CD41CD251FOXP31regulatory T cells increase de novo in kidney transplant patients after immunodepletion with Campath-1H. Am J Transplant 8: 793–802, 2008
Tang Q, Leung J, Melli K, Lay K, Chuu EL, Liu W, Bluestone JA, Kang SM, Peddi VR, Vincenti F: Altered balance between effector T cells and FOXP31 HELIOS1 regulatory T cells after thymoglobulin induction in kidney transplant recipients. Transpl Int 25:1257–1267, 2012
Bluestone JA, LiuW, Yabu JM, LaszikZG, Putnam A, BelingheriM, Gross DM, Townsend RM, Vincenti F: The effect of costimulatory and interleukin 2 receptor blockade on regulatory T cells in renal transplantation. Am J Transplant 8: 2086–2096, 2008 Lee SY, Lee SH, Yang EJ, Kim EK, Kim JK, Shin DY, Cho ML: Metformin ameliorates inflammatory bowel disease by suppressionof the STAT3 signalingpathwayandregulation of thebetween Th17/Treg balance. PLoS One 10: e0135858, 2015
Purroy C, Fairchild RL, Tanaka T, Baldwin WM 3rd, Manrique J, Madsen JC, Colvin RB, Alessandrini A, Blazar BR, Fribourg M, Donadei C, Maggiore U, Heeger PS, Cravedi P: Erythropoietin receptor-mediated molecular crosstalk promotes T cell immunoregulation and transplant survival. J Am Soc Nephrol 28: 2377–2392, 2017
Nazik Mahmoud
3 years ago
T cells play an important role in allorecognition through direct way by T cell receptors that recognise the donor HLA protein or by the indirect way where this donor HLA protein processed by Antigen presenting cells of the recipient that later recognised by TCR.
In the indirect activation of T lymphocytes ,the CD4 differentiate into 5 types:
Th1,Th2,Th17,Tfh and the most important Treg.
Treg necessary for preventing autoimmunity because it express high level of IL-2Ralfa.
Treg has four types T reg ,B reg,anergy and exhaustion.
Because Treg express high level of CD25 and transcription factor Foxp3 ,it play the main role that why if it suppressed,the immune tolerance will achieved
So the lymphocytes depleting agent like ATG is best option for immune tolerance.
saja Mohammed
3 years ago
T -cells populations:
T cells consider the main player in the induction of immune response.
1-Conventional T helper cells (Th) with subsets of cells (Th1, Th2, Th17, TFh ) they control the adaptive immunity by activating other effector cells such as CD8+ cytotoxic T cells, B cells and macrophages.
2-T regulatory cells with suppresser activity potentiate the suppressing of cytotoxic Th Cells and enhance the induction of tolerance. by ensuring self ⁄ non-self-discrimination.
T-cells activations:
Activation of T Cells is antigen dependent, initiated by APC s
It occurs through three signals signal mode
1-signal 1involve the contact of T cell receptor (TCR) -CD3 complex with MHC peptide complex
2- signal 2 through the costimulatory pathway in the presence of CD28which lead to T cell activation and proliferation to T cells, B7-2 (often known as CD80 or CD86) provides the second signal and prevents T cell to go into anergy.
3-signal3(cytokine production): It is a potent signal involving cytokine production mainly IL-2 that result in T lymphocyte maturation and differentiation into multiple effector subsets.
–Tregs) and their role with effector cells to identify the bases of immune tolerance.
Treg-cell activation is antigen-specific like the Th cells activation, but Treg cells suppressive activity Is an antigen-specific fashion.
Treg-specific molecular marker is still lacking, but Treg with foxp3 expressive marker which have both activating and suppressing effect it considers critical factor for Treg function, Treg cells induced by T-GFB Cytokines will lose FOXP3 expression and suppressive activity upon stimulation, Furthermore, based on recent evidence all CD4+, cd8+Tcells may upregulate FOXP3 with acquiring the suppressive effect upon activation so this lead to conclude the suppressive activity of FOXP3 not limited to T regulator cells ,and its true suppressive effect has been challenged .Additional to that the ability to suppress T cells is clearly not an exclusive property of Treg cells. The mechanism of suppression based on a three-partner interaction between the Treg cell, the Th cell to be suppressed, and the antigen presenting cell (APC). It is well established that conventional Th cell subsets suppress each other. In particular the subsets of conventional Th 1, Tfh, Th17).
Regulatory T cells that expressing CD4, CD25, and the FOXP3 expressive marker, are a highly suppressive population and count for 5% to 10% of CD4+ T cells .
Impact of approved immunosuppressive drugs on Treg:
1- Antithyroglobulin (ATG)
Deplete CD4+, CD8 in the first 3 months of induction therapy its action IL2 dependent apoptosis with induction of T CELL anergy at low doses, it act as antibody-dependent cellular cytotoxicity (ADCC) at moderate doses, and complement-mediated lymphocyte lysis at high doses
ATG is not only limited to T cell depletion, but also in relative preservation of Treg
especially at lower doses.
2-CNI, Cyclosporine, tacrolimus
CNI effect on Treg is dose and duration dependent.
CNIs impair Treg by directly inhibiting Treg activation, inhibiting the generation of pTreg,
and indirectly by limiting IL-2 production by Tconvs. Also inhibit Treg proliferation in a
dose-dependent fashion in vitro.
Low dose CNI can protect the patients from nephrotoxicity and spare the Treg cells function.
3-MMF treatment
promotes Treg expression over Th17 cells by inhibiting T cell Ig mucin-1 expression, a protein that promotes differentiation into effector T cells than Treg.most preclinical and -clinical evidence suggests that MMF is compatible with Treg homeostasis and function.
4-CORTICOSTERIODS
glucocorticoids promote Treg through multiple mechanisms, corticosteroids enhance the Treg prevalence and activity also may create a favorable immune environment for Treg through modulation of local cytokines expressive activities.
5-M-TOR inhibitors, also promote the Treg and its also dose dependent 6- Rituximab still need more studies to confirm its impact on Treg
References:
1- A- Gorthy, how do Regulatory T Cells Work? doi: 10.1111/j.1365-3083.2009.02308.
2-Rathore R, Gunawansa N, Sharma A, Halawa A (2017) Current State of Tolerance: The Holy Grail. Arch Clin Nephrol 3(2): 057-063. DOI ,http://dx.doi.org/10.17352/acn.00002 References:
3- Impact of immune-modulatory drugs on Treg
Akiko Furukawa, MD#, Steven A. Wisel, MD#, and Qizhi Tang, PhD
4- Up to date medicine function of T -cells .
5- -Handbook of kidney transplantation, Fifth edition.
Mahmoud Rabie
3 years ago
T cells represent about 60-70% of all lymphocytes in circulating blood, The role of T cells in transplantation is allorecognition. Allorecognition is the recognition of the donor alloantigen by the recipient T cells.
T cells have T cell receptors (TCR) on their membrane which is able to attach HLA molecule bounded to the antigenic peptide.
Allorecognition is divided into 2 types: 1- Direct allorecognition : the antigenic peptide is presented to T cells of the recipient by the donor APCs. 2- Indirect allorecognition : the donor antigen is presented to T cells by the host APCs.
T cell activation pass through three signals : 1/ Signal 1 is TCR signalling :
Engagement of TCR with the antigenic peptide attached to HLA molecule results in activation of calcineurin pathway and induction of cytokine gene. 2/ Signal 2 is costimulation :
Engagement of CD28 with members of B7 family. Both signal 1 and 2 will lead to initiation of signal 3. 3/ Signal 3 is cytokines production :
Cytokine production and and their interaction with the corresponding receptors will lead to cell division.
Cytokine production leads to differentiation of T cells into several types of effector T cells. CD4+T cells will differentiate into 4 sub types of T helper cells : Th1. Th2, Th17, Th FH and one regulatory subgroup Treg, while CD8+Tcells will differentiate into cytotoxic T cells, Also , cytokines help these effector T cells to be converted to memory T cells.
All these effector T cells produced as a result of T cell activation will participate in allograft rejection (either acute or chronic) so immunosuppressive drugs directed against these 3 signals of activation help in preserving the graft and preventing the rejection.
REF:
Handbook of kidney transplantation (sixth edition)
Mahmud Islam
3 years ago
T cells have a central role in the process of transplantation either in tolerance or rejection by recognition of foreign antigens. T cells have a role in activating and orchestrating the response. The allorecognition can be direct, indirect, or semidirect.
we have cytotoxic T cells that as their name implies kill their target directly after interacting of CD8 presented on them with MHC las I antigens.
T helper cells have wide range of effector functions. the have many subtypes like TH1, TH2, TH17, TfH and regulatory T cells. the have CD4.
After binding to class II MHC with CD4 the become activated and help shape activate the immune response by helping B cells produce antibodies.
Memory T cells provide immune response to previously encountered antigens. he have either CD4 or CD 8.
In short TH1 activate macrophages, TH2 activate eosinophils and mast cells, TH17 enhance neutrophis response, THfH enable B cells to develop into mast cells.
T regulatory cells on the other hand Suppresses other immune cells, particularly CD4+ and CD8+ responses. They use FOXp3 as transcription factor.
T cells play central role in transplant Immunology in case of transplant rejection.
Rejection passes through sensitization stage and Effector stage
Sensitization starts with Allorecognition in which T cells recognise foreign donor peptides , through its TCR then it become activated
Recognition occurs either directly through Recognition of MHC bound Donor antigens ,or indirectly through self APCs.
In normal individuals only 0.01 to 0.1 of individual lymphocytes are considered active , which in transplantation this ratio increases to 2-10% . ( which may be attributed to presence of memory T cells )
Naieve T cell requires 3 signals inorder to be activated and converted to Effector T cells :
1. Stimulation in which TCR interact with MHC peptide complex on APCs
2. Co Stimulation in which Co stimulatory molecules interact together ( CD28 on T cells , and CD B7-1 , CD B7-2 on APCs )
3. Cytokine release .
Early acute rejection of kidney allografts is essentially initiated by CD4+ T cells recognizing donor MHC class II molecules in a direct fashion
In addition, some studies suggest that these allografts could be rapidly infiltrated with recipient endogenous alloreactive effector memory T cells
Studies showed that T cells activated indirectly are responsible for chronic allograft rejection, either on their own or through the induction of alloantibody production by B cells .
regulatory T cells (Tregs) play an essential role by suppressing harmful inflammatory responses .
Tregs are CD4+CD25high T lymphocytes expressing FoxP3 , have an important role on inducing tolerance.
Hinda Hassan
3 years ago
What are the immunosuprressive medications that potentiate the tolerance function of Treg?
1- steroid expand steroid-related IL-2– dependent expansion of Tregs
2- mTOR expand and and increase Foxp3 expression but decrease with time.
3- alemtuzumab increase generation/expansion,
4- mmf variable
Paloma Leticia Martin-Moreno, Sudipta Tripathi and Anil Chandraker, Regulatory T Cells and Kidney Transplantation, CJASN Nov 2018, 13 (11) 1760-1764; DOI: 10.2215/CJN.01750218
Thanks Hinda for your contribution
Please watch the typos (MMF not mmf).
Hinda Hassan
3 years ago
1. Do you think that all subtypes of Treg have the same potential in induction of tolerance (you have to classify the Treg first)
Tregs are CD4+ cells which express high levels of the IL-2 receptor alpha chain CD25, beside the transcription factor Foxp3. There are many subtypes with functional heterogeneity.
Types of Tregs(Phenotypes) : thymus derived (natural) Tregs, or peripheral inducible Tregs. Inducible Tregs can be generated from natural Tregs or naïve CD4+CD25- cells . 1
Several types of Tregs were described: CD4+, CD8+, CD3+,CD4-,CD8-,file:///C:/Users/USER/AppData/Local/Temp/msohtmlclip1/01/clip_image002.gif , and NK T cells . CD4+CD25+Foxp3+ T cells was the most one studied.
Foxp3 importance was due to the fact it correlate with suppression activity , regulate the expression of CTLA-4, GITR, and CD25 on the Treg surface (used for identification of Treg)2
beside the subtypes , other factors which may influence tolerance include the number of cells needed to be infused, the frequency and timing besides the in vivo migration. Some subtypes produce IL-10 and IL-35, which can make other t cells tolerant (“infectious tolerance”)3 1- Paloma Leticia Martin-Moreno, Sudipta Tripathi and Anil Chandraker, Regulatory T Cells and Kidney Transplantation, CJASN Nov 2018, 13 (11) 1760-1764; DOI: 10.2215/CJN.01750218 2- Sacha A. De Serres, Mohamed H. Sayegh, Nader Najafian, Immunosuppressive Drugs and Tregs: A Critical Evaluation! CJASN Oct 2009, 4 (10) 1661-1669; DOI: 10.2215/CJN.03180509
3- Edozie, Francis C.1,2; Nova-Lamperti, Estefania A.1,2; Povoleri, Giovanni A.M.1,2; Scottà, Cristiano1,2; John, Susan2,3; Lombardi, Giovanna1,2; Afzali, Behdad1,2,4Regulatory T-Cell Therapy in the Induction of Transplant Tolerance, Transplantation: August 27, 2014 – Volume 98 – Issue 4 – p 370-379 doi: 10.1097/TP.0000000000000243
saja Mohammed
3 years ago
-T lymphocyte is the main player in the rejection .
– naive T cells priming in the secondary lymphoid tissue by the APC s mainly the dendritic cells then the cells will be activated and differentiate to the subsets of T effectors cells which involved in rejection by different pathways direct pathway via cytotoxic T cells activation and indirectly by attracting and activating macrophage and granulocytes
Also they helped the B cells to produce Allo antibodies .
Memory T cells they directly migrate to the graft and generate effectors in place
Allo reactive T memory cells are prevalent in humans and experimental animals who have never received A-graft.
also T memory cells are less susceptible to most immunosuppressive therapy due to the TCR cross reactivity there fore. Further Understanding about the effector T cells and T memory cells interactions and their dynamic behavior and effects in rejection
the use of new technology called 4D multiphotone intravital Micrscopy
To assess in real time the immune response of both the effector and T memory cells by 4D imaging In the living allograft This led to discovery that in acute rejection both the T effector and T memory cells migration is antigen driven immune response and not by chemokine effect and that dendritic cells called passengers leucocytes reach into capillary lumen to capture T cells .
Also the host Dendritic cells Derive from the host monocytes expressed and migrate in to allograft and acquire DC morphology they continuously interact with the captured antigen specific T cells and maintain their activation {survival and proliferation} in the graft and associated with graft rejection .
References
Four-Dimentional Imaging of T cell in kidney transplant rejection ,review , http://www.jasn.org.
AndrewD .Hughes,FadiGLakkis , and MartinH .Oberbarmscheidt
Assafi Mohammed
3 years ago
Role played by T cells in transplant immunology: 1.Allorecognition:T cells are central to the process of transplant rejection through allorecognition of foreign antigens. direct T cell allorecognition; Native T cells located in LNs become activated through recognition of allogeneic MHC molecules displayed on donor passenger leukocytes(dendritic cells (DCs)).
Indirect Allorecognition; allogeneic MHC class I antigens could be presented by self-MHC class I on antigen-presenting cells (APCs) and trigger the activation of some CD8+ cytotoxic T cells in vitro, a phenomenon referred to as cross-presentation.
allogeneic MHC peptides were regularly presented by self-MHC class II molecules on recipient APCs and triggered the activation of CD4+ T cells in the LNs of skin-grafted mice {Benichou G, Takizawa PA, Ho PT, Killion CC, Olson CA, McMillan M, et al. Immunogenicity and tolerogenicity of self-major histocompatibility complex peptides. J Exp Med (1990) 172(5):1341–6. doi:10.1084/jem.172.5.1341}
Acquisition of donor antigens by recipient APCs may occur in the graft itself or in the host lymphoid organs through pinocytosis of shed donor proteins, phagocytosis of dead donor cells and apoptotic bodies, or via transfer of donor antigens through cell–cell contact or phagocytosis of extracellular vesicles secreted by donor cells. {Front. Immunol., 14 December 2016 | https://doi.org/10.3389/fimmu.2016.00582 Allorecognition by T Lymphocytes and Allograft Rejection Jose Marino, Joshua Paster and Gilles Benichou}
Semi-Direct Allorecognition :leukocytes exchange molecules, including RNA and proteins, either via cell–cell contact (trogocytosis), nanotubes, or through the release of extracellular vesicles such as exosomes.
T cells were shown to acquire surface immunoglobulin molecules from B cells (42) and antigens from macrophages.
Acquired peptide–MHC complexes have been shown to remain at the cell surface of APCs for more than 48 h, providing ample opportunities for T cell activation.
2.Alloresponse: allorecognition of foreign antigensleading to T-Cells activation, and the orchestration of an effector response that results in organ damage.
Direct and indirect allorecognition represent distinct mechanisms involving different APCs, T cells, and antigen determinants. Each of these pathways can sufficiently and exclusively lead to acute rejection of fully allogeneic skin allografts.
In certain circumstances, T cells activated directly and indirectly could either cooperate or suppress each other, a process influencing the survival of allografts.
It is plausible that in recipients of MHC class I-disparate allografts, CD4+ T cells activated exclusively through indirect allorecognition provide help [via IL-2 and gamma interferon (γIFN) secretion] for the direct activation of other CD4+ T cells (three-cell cluster model) or the differentiation of CD8+ cytotoxic T cells recognizing donor MHC class I peptides in a direct fashion (four-cell cluster model) . Likewise, in the absence of bone marrow-derived donor professional APCs, T cells recognizing donor MHC class I or II directly on parenchymal cells can receive costimulatory signals via interaction with CD80/86 or CD40 located on recipient professional APCs (activated through indirect presentation to T cells) (trans-costimulation). At the same time, early inflammatory direct alloresponses associated with γIFN and tumor necrosis factor alpha production and subsequent induction of donor MHC class II expression on endothelial cells presumably enhances allo-MHC antigen processing by recipient APCs and indirect activation of T cells. Therefore, the direct and indirect alloresponses can act synergistically to reject an allograft.
3.Induction of tolerance: Long-term transplant acceptance in the absence of immunosuppressive therapy remains the ultimate goal in the field of transplantation and many studies are exploring potential therapies. One promising cellular therapy is the use of regulatory T cells to induce a state of donor-specific tolerance to the transplant.
Allograft tolerance, defined as long-term survival of allogeneic transplants in the absence of ongoing immunosuppressive drug treatment, can occur via deletion or inhibition of alloreactive T cells.
Tolerance can occur naturally, as seen in the tolerance of paternal alloantigens expressed by the fetus during pregnancy.
Immune-privileged tissues such as the central nervous system and the testis are tolerogenic in that they elicit systemic tolerance to foreign antigens to which they are exposed.
Various cells and mediators of the innate and adaptive immune systems have been implicated in the process of allograft tolerance. Among them, regulatory T cells (Tregs) play an essential role by suppressing inflammatory responses.
MICHAEL Farag
3 years ago
Role of T lymphocytes in transplantation
recipient T cells recognize the MHC–peptide complex through the T cell receptor (TCR)
A given T lymphocyte, however, expresses a handful of different TCRs on its surface, allowing it to respond to a limited number of antigens. Normally, anywhere between 0.01% and 0.1% or less of an individual‘s T lymphocytes recognize and respond to a given microbial antigen but in the setting of transplantation, approximately 2% to 10% of T lymphocytes react to the mismatched organ. There are two main reasons for the high prevalence (precursor frequency) of alloreactive T lymphocytes. First, TCRs recognize alloantigens via two pathways:
Direct allorecognitionrefers to the recognition by TCRs of intact donor HLA proteins that are foreign (allogeneic) to the recipient, whereas indirect allorecognitionrefers to the recognition by TCRs of donor alloantigens (whether HLA or mHA) that are processed by recipient APCs
and presented as small peptides bound to self- (recipient) HLA molecules—the same pathway responsible for presenting microbial antigens.
The second reason for the high frequency and potency of alloreactive T lymphocytes is the conspicuous presence of memory T lymphocytes in the alloreactive T-lymphocyte repertoire of humans. Memory T lymphocytes share the same
antigenic specificity as their naïve precursors but are present in much higher frequency and have a much greater proliferative capacity once activated by antigen.
T cells cause allograft rejection either by eliciting a DTH response or through cytolytic/cytotoxic activity
CD8+ CTLs are the major players in lymphocyte-mediated cytotoxicity, and they predominate the cellular infiltrates in acutely rejecting grafts [41] . CD8+ CTLs are primed and activated by recognition of donor MHC class I molecules primarily on donor APCs, but also on vascular endothelial cells
Nadia Ibrahim
3 years ago
What is the role played by T cells in transplant immunology?
T cells are lymphocytes that constitute a major component of acquired immunity.
In transplantation T cells orchestrates the cascade of graft allorecognition resulting in either rejection ( Acute or choronic), or tolerance (allograft acceptance)
T cell allorecognition is the Recognition of donor antigens (allogeneic MHC molecules) by recipient T cells (Allospecific T cells, alloreactive T cells, effector)
(1).
alloreactive T cells are stimulated through one of 3 pathways ( pathways of allorecognition):
Direct Allorecognition
Donor dendritic cells (DCs) (passenger leukocytes) that carry Doner specific HLA , migrate through lymphatics to host regional lymph nodes (LNs) and got recognized through Naïve T cells located in these LNs and trigger the activation of CD8+ cytotoxic T cells inducing rapid and acute cellular rejection (2)
Indirect Allorecognitiondonor antigens are taken up and processed by recipient APCs and presented by self-MHC class II to trigger the activation of CD4+ T
Semi-Direct Allorecognition
Doner MHC class I and II molecules are expressed on cell surface of recipient APCs without being processed, this is done through exchange molecules (MHC cross-dressing) between recipient and donor DCs after transplantation either via cell–cell contact (trogocytosis), nanotubes, or through the release of extracellular vesicles such as exosomes Resulting in T cell activation (3).
In certain circumstances, T cells activated directly and indirectly could either cooperate or suppress each other, a process influencing the survival of allografts.
T Cell Allorecognition Pathways in Regulatory Tolerance
Allograft tolerance, defined as long-term survival of allogeneic transplants in the absence of ongoing immunosuppressive drug treatment, can occur via deletion or inhibition of alloreactive T cells.
Among them, regulatory T cells (Tregs) play an essential role by suppressing inflammatory responses . Tregs are CD4+CD25high T lymphocytes expressing FoxP3 transcription factor either constitutively (thymic Tregs or tTregs) or after peripheral recognition of antigens (peripheral Tregs or pTregs) (4). In addition to their role in self-antigen tolerance, both Treg subsets can suppress inflammatory alloreactive T cells in vitro and in vivo..
References
(1) Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol (2003) 3(3):199–210. doi:10.1038/nri1027 (2) Rosenberg AS, Singer A. Cellular basis of skin allograft rejection: an in vivo model of immune-mediated tissue destruction. Annu Rev Immunol (1992) 10:333–58. doi:10.1146/annurev.iy.10.040192.002001 (3) Dolan BP, Gibbs KD Jr, Ostrand-Rosenberg S. Dendritic cells cross-dressed with peptide MHC class I complexes prime CD8+ T cells. J Immunol (2006) 177(9):6018–24. doi:10.4049/jimmunol.177.9.6018 (4) Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell (2008) 133(5):775–87. doi:10.1016/j.cell.2008.05.009
MOHAMMED GAFAR medi913911@gmail.com
3 years ago
T cells are mainly produced in the thymus and were first recognized as lymphocytes that do not express surface Ig or genes for Ig . The hallmark of a T cell is expression of an antigen-recognizing T cell receptor (TCR).
There are two forms of TCRs, an a- and b-chain TCR (TCRa,b) expressed by 95% of peripheral T cells , and a g- and d-chain TCR (TCRg,d).
TCR, unlike antibody, does not directly bind to unprocessed antigen. TCR recognizes peptides of antigen presented by MHC present on cell membrane.
To activate T cells, antigen-presenting cells (APCs) must first be activated by the antigen and induced to express MHC and costimulatory molecules. APCs are activated by bacterial wall molecules or virus materials, such as double-stranded DNA, that bind to Toll-like receptors,This leads to production of inflammatory mediators, such as TNF-a, IL-1b, and PGE2, which further activate APCs
The majority of peripheral TCRa,b T cells is effector programmed to become soldiers. A minority of peripheral CD41 TCRa,b Τ cells released from the thymus expresses CD25 and FOXP3, and they are professional Tregs or spies. Both effector T cells and Tregs have a vast array of TCR to recognize a broad repertoire of specific antigen.
How is t cell activated?
Signal 1: TCR Signaling,
Binding of antigen (HLA–peptide complex) to the TCR triggers a signaling cascade that leads to Tlymphocyte activation.
Signal 2: Co-Stimulation ,
engagement of co-stimulatory receptors on T lymphocytes by their ligands on APCs
Signal 3: Cytokines,
Cytokines involved in T-lymphocyte activation are proteins secreted by mature APCs or the T lymphocytes themselves. They serve two main purposes in the context of T-lymphocyte activation: they stimulate Tlymphocyte proliferation and induce the differentiation of T lymphocytes into multiple effector subsets that have distinct phenotypes and functions
A-Interleukin-2 (IL-2) is the first T-lymphocyte mitogen to be discovered by virtue of its strong capacity to induce Tlymphocyte proliferation in culture.
IL-2 is produced by antigen-activated T lymphocytes and acts on the same lymphocytes that produce it (autocrine) or on neighboring lymphocytes (paracrine). Naïve T lymphocytes express a low-affinity form of the interleukin-2 receptor.
WHAT ARE THE TYPES OF T LYMPHOCYTES.?
A-Th1 lymphocytes are the prototypical lymphocyte subpopulation responsible for rejection. Their differentiation is driven by IL-12 and interferon-gamma (IFNγ).
B-Th2 lymphocytes are the lymphocyte subset responsible for allergic reactions. They also contribute to allograft rejection.
C-Th17 lymphocytes constitute a subpopulation that is particularly adept at responding to fungal infections.
D-TFH (follicular helper) lymphocytes play a key role in antibody production by providing help to B lymphocyte
E-Cytotoxic T lymphocytes (CTL) bind via their TCRs to target cells expressing nonself MHC–peptide complexes and induce target cell killing by secreting perforin and granzymes
MEMORY T LYMPHOCYTES
A large number of effector lymphocytes are generated during an immune response, but most undergo activation-induced cell death by apoptosis as the response progresses. The few effector lymphocytes that survive give rise to memory T lymphocytes (TM).
Tregs which are responsible for induction of tolerance.
Acute cellular rejection is T cell–mediated and involves CD41 and CD81 T cells.
REFEERENCE
CJASN ePress. Published on April 15, 2015 as doi: 10.2215/CJN.06620714
Last edited 3 years ago by MOHAMMED GAFAR medi913911@gmail.com
fakhriya Alalawi
3 years ago
The presence of memory T cells has been often correlated with poor outcomes in clinical transplantation. In humans, the presence of memory T cells pre-transplantation has been associated with an increased risk for acute rejection of kidney transplants. 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 in heart-transplanted mice, and CD8+ T cell depletion or limiting their trafficking into the graft significantly extends allograft survival.
Early direct contact of circulating memory CD8+ T cells with donor endothelium up-regulates 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 cardiac allografts within hours after reperfusion. Once in the graft parenchyma, these memory CD8+ T cells proliferate extensively, up-regulate the expression of ICOS, and secrete IFNγ in an ICOS-dependent manner.
Reference:
Benichou G, Gonzalez B, Marino J, Ayasoufi K, Valujskikh A. Role of memory T cells in allograft rejection and tolerance. Frontiers in immunology. 2017 Feb 28;8:170.
Mujtaba Zuhair
3 years ago
T lymphocytes plays an important role in transplantation . Naïve T cells can be stimulated either by direct pathway ( through donor antigen presenting cells ) or by indirect pathway ( through recipient APCs) . Once stimulated , it transforms to either : Cytotoxic T lymphocytes : which can destroy cells harboring the target antigen by by inserting perforins and granzymes into the cells . Helper T lymphocytes : Which orchestrates the adaptive immune system . These cells can secret cytokines and activates B cells to become plasma cells . Many subtypes of T helper lymphocytes: TH1 Lymphocytes : secrets interferon and TNFa which can lead to graft damage directly, also it activate macrophages, stimulate Cytotoxic T lymphocytes, stimulate the differentiation of B cells into immunoglobulin producing plasma cells. TH2 Lymphocytes : secret cytokines Iike IL4, IL5 , IL10 which activates mast cells and basophiles . TH2 can suppress TH1 lymphocytes. TH17 Lymphocytes : secretes IL17, which leads to attraction of inflammatory cells to the graft. Tfh Lymphocytes: T follicular helper lymphocytes stimulate B cell to differentiate to plasma cells through CD40- CD40L and produce IL4, IL21. T regulatory Lymphocytes (Fox3 +): These cells can suppress T helper and T cytotoxic Lymphocytes and can induce tolerance to the graft . It has 2 subtypes :
Thymus (natural) Treg and peripheral inducible Treg.
Regarding drug effect on Treg : CNI reduce Treg population.
mTOR inhibitors increase the population of Treg.
ATG increase Treg T lymphocytes ratio.
Belatacept reduces Treg.
IL2 increase Treg population.
Metformin increases Treg population.
Erythropoietin inhibit T cells but spares Treg.
References :
(1) Handbook of Kidney Transplantation, SIXTH EDITION
(2) Paloma Leticia Martin-Moreno, Sudipta Tripathi, and Anil Chandraker
Regulatory T Cells and Kidney Transplantation
Clin J Am Soc Nephrol 13: 1760–1764, 2018. doi: https://doi.org/10.2215/CJN.01750218
Amit Sharma
3 years ago
What is the role played by T cells in transplant immunology?
T cells are the backbone of the graft rejection by virtue of their role in allorecognition of antigen with costimulation, leading to their activation and production of inflammatory mediators, causing graft damage.
The 3 different pathways involving allorecognition are: (1)
1) The direct pathway involves the recognition of donor antigen presenting cell (APC) having MHC-peptide complex by the recipient T cell leading to activation of CD4+ and CD8+ T cells. This pathway has important role in the initial period of transplant, leading to early onset acute rejection which is cellular, involving mainly the interstitium and tubules.
2) The indirect pathway involves the recipient APC presenting the donor peptide to recipient CD4+ T cells via MHC class II, interacting with B cells leading to antibody formation. It is responsible for late onset rejection, especially chronic rejection and predominantly vascular damage.
3) The semi-direct pathway involves priming of CD4+ and CD8+ T cells by the donor MHC-peptide complex acquired by the recipient APC through direct cell to cell contact or from exosomes secreted by the donor APC (cross-dressing).
Once allorecognition happens, T cell activation takes place by 3 signals. (2)
Signal 1: Stimulation – The T cell receptor (TCR) on the CD4 and CD8 cell interacts with the antigen on the MHC molecule
Signal 2: Co-stimulation – Interaction between CD28 ( on T cell) and CD80/86 on the APC
Signal 3: Cytokine production – especially IL-2 leads to T cell maturation and differentiation
The immune response involves stimulating both the naive T cell as well as the memory T cells. Memory T cells can survive even in absence of antigen and can be activated without co-stimulation. They are more resistant to apoptosis and rejection caused by them is resistant to treatment with immunosuppressives and lymphocyte depleting agents.
T cells differentiate into a number of subsets, each having unique functions. (3)
CD4+ T cells: give rise to T helper cells and T regulatory cells CD8+ T cells: give rise to cytotoxic T cells.
T helper cells:
1) Th1: responsible for cell-mediated immunity. It releases gamma interferon and TGF-beta leading to CD8+ cytotoxicity (using perforin/granzyme pathway), macrophage dependent delayed type hypersensitivity and IgG2a synthesis from B cells activating complement lading to rejection. It also has FasL pathway with cytotoxic activity.
2) Th2: responsible for humoral immunity. It releases IL-4, 5,9, 10 and 13, stimulating B cells and eosinophils leading to graft rejection.
3) Th17: release IL-17, 21 and 22 leading to neutrophil recruitment to the rejection site and hence has role in early post transplant period acute rejection.
4) Tfh: Follicular helper T cells help in conversion of activated B lyphocytes to antibody generating plasma cells.
T regulatory cells (Treg): T cells with regulatory or immunosuppressive action. They control immune homeostasis by maintaining immune tolerance against self-antigen. There are multiple mechanisms of action of Treg, including: (4)
a) Contact-independent anti-inflammatory cytokine (IL-10, IL-35 and TGF beta) production, and exosome formation leading to specif gene silencing.
b) Contact dependent suppression through interaction of CTLA4 on T reg with CD80/86 on APC, restricting T cell access to signal 2.
c) Inducing apoptosis using Fas/FasL and Granzyme/perforin pathways.
d) Disruption of metabolic pathways via CD39, causing decreased ATP triggered proinflammatory signals.
The CD8+ T cells are responsible for graft destruction by apoptosis due to cytotoxic activity.
References:
1) Dewolf S, Sykes M. Alloimmune T cells in transplantation. J Clin Invest 2017;127:2473-2481.
2) Priyadarshini B, Greiner DL, Brehm MA. T cell activation and transplantation tolerance. Transplant Rev (Orlando) 2012;26:212-222.
3) Issa F, Schiopu A, Wood KJ. Role of T cells in graft rejection and transplantation tolerance. Expert Rev Clin Immunol 2010;6:155-169. 4) Vaikunthanathan T, Safinia N, Boardman D, et al. Regulatory T cell: tolerance induction in solid organ transplantation. Clin Exp Immunol 2017;189:197-210.
Ahmed Omar
3 years ago
T cells are the backbone of the human adaptive immune response. The develop from hematopoietic stem cell ,migrate to Thymus to continue their antigen independent maturation.
Alloreactive T cells play a central role in transplantation: they are key mediators of rejection, tolerance and GVHD.
T cell activation:
It is the process in which naïve T cell become activated into effector T cell
APC(dendritic cells play a prominent role) is capable to present antigen bound to MHC to naïve CD4 (T-helper) or CD8 (T –cytoxic).
First signal(stimulation signal): The CD4 and CD8 T cells detect the alloantigens expressed on the foreign graft cells through their T-cell receptors. The T cell receptor interacts with the antigen given by MHC molecules
Second signal(Co-stimulation signal): the interaction between co stimulants mainly CD28 on the T cell surface with its APC surface ligands, B7-1 or B7-2 (often known as CD80 or CD86) provides the second signal and prevents T cell to go into anergy.
Third signal( cytokine production):It is a potent signal involving cytokine production mainly IL-2 that result in T lymphocyte maturation and differentiation into multiple effector subsets.
T lymphocytes populations and functions:
CD4 T lymphocytes differentiate into 4 helper subpopulation(TH1,TH2,TH17, Tfh) and one regulatory subpopulation(T reg), while CD8 T lymphocytes differentiate into cytotoxic T lymphocytes that can kill cells by production of perforin and granzymes.
TH1:responsible for graft rejection through production of IFN gamma, TNF alpha these activate macrophages, activate B lymphocytes to produce complement fixing IgG AB and stimulate differentiation of CD8 T cells to cytotoxic T cells
TH2: responsible for allergic reactions and also contribute to allograft ejection though production Of AB that do not fix complement(less potent than TH1)
TH17: produce IL17 that can cause graft rejection by promoting inflammation and formation of tertiary lymphoid tissue at the inflammation site
Tfh (follicular): provide help for activated B lymphocyte to differentiate to AB producing plasma cells plasma cells
Memory T lymphocytes: few effector lymphocytes give rise to memory T cells which have longer life span, wider migration pattern, lower threshold for activation than naïve T cells with a stronger immune response that is partially responsive to co-stimulatory pathways as B7-CD28
Regulatory T cells (Tregs): They are specialized subpopulation of T cells that inhibit T cell proliferation ,cytokine production, preventing autoimmunity and down-regulate the allo-immune response. So simply they are in charge of suppressing potentially deleterious activities of Th cells.
Finally we conclude that the stimulatory activities of T cells need to be counterbalanced by suppressive mechanisms, in order to fine-tune immune responses.
· How do Regulatory T Cells Work?. A Corthay. Scand J Immunol. 2009 Oct; 70(4): 326–336
· Alloimmune T cells in transplantation. Susan DeWolf and Megan Sykes.The Journal of clinical investigations. J Clin Invest. 2017;127(7)
Hand book of kidney transplantation sixth edition
The immune response to a transplanted organ consists of both cellular (lymphocyte mediated) and humoral (antibody mediated) mechanisms.
T cells are the maestro in the rejection of grafts.
T cells recognize antigen by different pathways
Direct pathway
T cells of the recipient directly recognize intact allo-MHC molecules on the surface of the donor cell.
The transplanted organ carries APCs in the form of interstitial dendritic cells with high density of allo-MHC molecules which can directly stimulate recipient’s T cells.
number of T cells that proliferate on contact with allogeneic donor cells is extraordinarily high as compared with the number of clones that target antigen presented by self-APC. Thus, this pathway is important in acute allorejection.
Indirect pathway
In the indirect pathway, T cells recognize processed alloantigen presented as peptides by self-APCs.
This pathway is involved in chronic allograft vasculopathy.
Semidirect pathway
The recipient antigen-presenting cell acquired intact donor MHC- peptide complexes via cell to cell contact or exomes and present them to the recipient T cell.
rejection consists of the sensitization stage and the effector stage.
Sensitization phase :
Foreign graft cells expresses alloantigens that are recognised by TCRs on the CD4 and CD8 T cells of recipient.
Two signals are needed for recognition of an antigen;
the first is provided by the interaction of the TCR with the antigen presented by MHC molecules,
the second by a costimulatory receptor/ligand interaction on the T cell/APC surface.
One of the most effective costimulatory pathways is the interaction of CD28 on the T cell surface with its APC surface ligands, B7-1 or B7-2 (commonly known as CD80 or CD86, respectively) .
Other costimulatory molecules include the CD40 and its ligand CD40L (CD154).
Also cytotoxic T lymphocyte–associated antigen-4 (CTLA4) also binds to these ligands and provides an inhibitory signal.
Effector stage
Alloantigen-dependent and independent factors contribute to the effector mechanisms.
Initially, injury responses as IRI induce a nonspecific inflammatory response which is not antigen dependent.
Following activation T cells differentiate into multiple effector populations, the effector cells are either CD4+ T helper or CD8+ cytotoxic T cells.
After activation, CD4-positive T cells initiate macrophage-mediated delayed type hypersensitivity (DTH) responses and provide help to B cells for antibody production.
T cells and T cell-derived cytokines such as IL-2 and TNF-α, inducible nitric oxide synthase (iNOS) and growth factors are upregulated early after transplantation also play a role in this process.
The growth factors, including TGF-ß and endothelin causes interstitial fibrosis, and glomerulosclerosis.
CD8-positive T cells is responsible for CMR either directly or by inducing apoptosis.
Prashant Malhotra,Immunology of Transplant Rejection. (2019 )
Ala Ali
Admin
3 years ago
Could anyone describe the T and B cells crosstalk during an immune response and how this affects the response to immunosuppression!?
recipient APCs process and present donor antigen to CD4 which recognize MHC II on APCs, also activated CD4 will stimulate B cell to produce antibodies to initiate the complement cascade and start the process of inflammation and rejection.
Cross-talk between T & B cells in transplantation is increasingly recognized as being important for alloimmune response. T cells activation of B cells occur through 3 signal pathway, initial B cell activation is driven by alloantigen. Mature B cells can recognize alloantigen through B cell receptor( signal 1). The second signal is costimulation, a cognate interaction between Th cells and B cells gives multiple costimulation signals for B cell activation. After that B cell activation require cytokines for their activation ( signal 3) produced by various T helper cells including Th1, Th2, Th17. In addition Tfh is required for B cells activation.
There are number of drug therapies which can affect T-B cells cross talk including: costimulatory blockade Belatacept, CD40 ligand blockade, Anti LFA1 blockade ( Efalizumab), Belimumab, Atacicept.
Reference:
Kwun J.,Manook M., Page E., Burghuber Ch., et al. Crosstalk Between T and B Cells in the Germinal Center After Transplantation. Transplantation 2017;101: 704–712.
Classical example is indirect allorecognition ; where recipient APC presents donor particles to the recipient Cd4. Cd4 get activated and stimulate B cells to differentiate in plasma cells which produces antibodies. Maintenance of high levels of immunosuppression is necessary.
Ala Ali
Admin
3 years ago
Dear all, Please consider the following in responding to this scenario: T cell population T cell activation, and T cells effector mechanisms
Mahmoud Hamada
3 years ago
T cell paly a principal role in recognition of transplanted graft.
there are 2 main pathways:
Direct one: recipient T cells detects whole MHC of donor cells. . This is the main pathway of early rejection due to excess number of T cells.
Indirect one: in this mechanism , T cells only recognize allo molecule after processed with host APC. This is the main mechanism of chronic rejection.
Doaa Elwasly
3 years ago
T cells are the main cells of the adaptive immune response for organ transplants,they are the modurator of tolerance, rejection, and Graft versus host disease
T cell undergo allorecognition through 3 pathways
–Direct pathway :T cells reacting directly to antigens presented by donor antigen-presenting cells (APCs) ,leading to acute rejection
–Indirect pathway :T cells recognize self-APCs presenting peptides on self-HLA molecules, from donor MHC antigens leading to chronic rejection as donor APCs present in the graft are subsitituted by the recipient APC later on .
Interactions between alloreactive B cells with immunoglobulin receptors that bind donor HLA molecules and presnts it to indirectly alloreactive T cells ,recognizing the peptides from the same allogeneic HLA molecules facilitating antibody production by B cells
– Semidirect pathway : allogeneic HLA/peptide complexes from donor cells named “cross-dressing,” activate T cells
A study recognised that high numbers of recipient APCs acquire donor MHC molecules via microvesicles,triggering the semidirect pathway to cause rejection
DeWolf S and Sykes M. Alloimmune T cells in transplantation: J Clin Invest. 2017;127(7):2473–2481.
The scenario here is about T cells and their functions NOT on allorecognition pathways
Weam Elnazer
3 years ago
T cells play a key role in transplant rejection by also recognizing foreign antigens, activating them, and orchestrating an effector response that causes organ damage.
Cellular (lymphocyte) and humoral (antibody) immunological responses to transplanted organs exist. While other cell types are involved, T cells are crucial in transplant rejection. The rejection response has two stages: sensitization and effector.
Sensitization
The CD4 and CD8 T cells detect the alloantigens expressed on the foreign graft cells through their T-cell receptors. The T cell receptor interacts with the antigen given by MHC molecules, and the costimulatory receptor/ligand interaction on the T cell/APC surface provides the second signal.
The interaction of CD28 on the T cell surface with its APC surface ligands, B7-1 or B7-2 (often known as CD80 or CD86) has been investigated the most.
Also, CTLA4 binds to these ligands and inhibits them. Other costimulatory molecules include CD40 and CD40L.
Direct pathway
In the direct pathway, host T cells recognize intact allo-MHC molecules on the surface of the donor or stimulator cell. Mechanistically, host T cells see allo-MHC molecule + allo-peptide as being equivalent in shape to self-MHC + foreign peptide and, hence, recognize the donor tissue as foreign. This pathway is presumably the dominant pathway involved in the early alloimmune response.
Indirect pathway
In the indirect pathway, T cells recognize processed alloantigen presented as peptides by self-APCs. Secondary responses such as those that occur in chronic or late acute rejection are associated with T cell proliferative responses to a more variable repertoire, including peptides that were previously immunologically silent. Such a change in the pattern of T cell responses has been termed epitope switching or spreading.
Clarkson MR, Sayegh MH. T-cell costimulatory pathways in allograft rejection and tolerance. Transplantation. 2005 Sep 15. 80(5):555-63. [Medline].
T- cells are subdivisions of lymphocytes that are responsible for immunity and defence mechanisms. also, T cells include some subtypes as T- helper, T cytotoxic, T- regulatory …. etc. each subtype is responsible for some specific final effects.
in transplant, immunology is the major impact for graft rejection and particular handling and interruption of some mechanisms are the major determinants of graft survival.
T- helper is the major coordinator of transplant immunology. it mediates its effects by controlling the activity of other immune cells via some specific mediators. therefore, it is the major target of some immunosuppressives used in transplantation. it has many roles in development of graft rejection.
T- regulatory cells mediate some opposite effects to avoid excessive immune responces. it has a very important role in transplant tolerance.
T- cytotoxic cells mediate direct cell cytotoxicities and are important in controlling viral infections and also development of tumors.
Multiple other actions are mediated by these cells and some steps are targets of some drugs used in transplantations.
Dear Dr Ibrahim
This is impressive if this was your refection just before reading. Even if with reading, you summarised very well. Excellent, keep going
Alyaa Ali
3 years ago
The immune response to graft is by three phases : allorecognition , activation of antigen specific lymphocytes and the effector phase of graft rejection
T cells are the mediator of rejection and they are the backbone of human adaptive immune response T cell activation : T cell recognition of antigen is the primary event that initiates the the immune response
Allorecognition :T cells recognize antigen in the form of peptide bound to major histocompatibility complex (MHC) proteins and this need two signals: signal 1 is by the interaction of the T cell receptor (TCR) with antigen presented as a peptide by the antigen-presenting cell (APC), and Signal 2 is provided by costimulatory receptor interaction on the T cell/APC cell surface .
Allorecognition can be divided into three pathways: direct, indirect, and semidirect pathways
Direct pathway:donor antigen-presenting cells (APCs) interact directly with recipient T cells .
Indirect pathway :recipient APCs present processed donor allogeneic peptides to recipient T cells.
Semidirect pathway : recipient APCs acquire donor HLA molecules that present peptides directly to recipient T cells.
once T cell activated , they undergo proliferation and differentiation , these activated T cell will induce CD8 T cell-mediated cytotoxicity, give help to B cell to produce antibodies and finally give help for macrophages to induce delayed-type hypersensitivity response References
Susan DeWolf , Megan Sykes .Alloimmune T cells in transplantation.J Clin Invest. 2017;127(7):2473-2481.
Ali JM, Bolton EM, Bradley JA, Pettigrew GJ. Allorecognition pathways in transplant rejection and tolerance. Transplantation. 2013;96(8):681–688.
Afzali B, Lechler RI, Hernandez-Fuentes MP. Allorecognition and the alloresponse: clinical implications. Tissue Antigens. 2007;69(6):545–556.
Lakkis FG, Sayegh MH .Memory T cells: a hurdle to immunologic tolerance.J Am Soc Nephrol. 2003;14(9):2402
Pratt JR, Basheer SA, Sacks SH . Local synthesis of complement component C3 regulates acute renal transplant rejection.Nat Med. 2002;8(6):582.
Lee RS, et al. Indirect recognition of allopeptides promotes the development of cardiac allograft vasculopathy. Proc Natl Acad Sci U S A. 2001;98(6):3276–3281.
Pietra BA, Wiseman A, Bolwerk A, Rizeq M, Gill RG. CD4 T cell-mediated cardiac allograft rejection requires donor but not host MHC class II. J Clin Invest. 2000;106(8):1003–1010.
Last edited 3 years ago by Alyaa Ali
Esmat MD
3 years ago
Allorecognition, that is defined as recognition of the donor alloantigen by the recipient T cell is a central event in the initiation of alloimmune response and eventually allograft rejection. The allorecognition needs to alloreactive T lymphocytes that express TCR capable of binding alloantigens.
There are vastly divers TCRs that recognize millions of alloantigens, but a given T lymphocyte, expresses a few different TCRs on its surface, allowing it to respond to a limited number of antigens.
Normally only 0.01%-0.1% of T lymphocytes of a patient recognize and response to a given microbial antigen, but in the context of transplantation, approximately 2%-10% of T lymphocyte react with mismatched allograft. Two main reasons were described for this discrepancy.
First, TCRs recognize alloantigens via three pathways: direct allorecognition, semi direct allorecognition, and indirect allorecognition. (Indirect pathway allorecognition is responsible for present microbial antigens). Allorecognition via the direct pathway are more prevalent (approximately 100 folds) compared to allorecognition via the indirect pathway (because of intrinsic bias and cross-reactivity). Direct allorecognition by T cells of intact MHC molecules has not demonstrated out of alloimmunity. So, this phenomenon uniquely distinguishes between alloimmunity from ordinary immunity to microorganisms and probably this pathway is the dominant pathway involved in early alloimmune response. Thus, direct recognition is of major importance in acute allorecognition and transplant organ that carries a high number of APCs (interstitial dendritic cells) have high intensity of allo-MHC molecules and can directly stimulate the recipient’s T cells. In the indirect pathway, T cells recognize processed antigens presented as peptides on self APC (host APC). Allopeptide-reactive T cells are present during both acute and chronic rejection. Even though primary immune responses are characterized by T cell-proliferative responses to a limited number of immunogenic MHC allopeptides, secondary responses such as those that occur in chronic or late acute rejection are associated with T cell-proliferative responses to a more variable repertoire. Such a change in the pattern of T cell responses has been termed epitope switching or spreading
Semi direct pathway: Intact donor antigen can be transferred between different T cell types, raising the possibility that direct T cell recognition of intact donor alloantigen on recipient APCs may also occur.
The second reason is the enormous presence of memory T lymphocytes in the alloreactive T lymphocyte repertoire of humans, which compared to their naïve precursors, are present at much higher frequency and have a much greater proliferative capacity once activated by antigens.
Activation of T lymphocytes requires two key signals: signal 1, interaction of TCRs with antigens presented by APC, and signal 2, costimulatory ligand/receptor interaction on T cell/APC cell surface (such as CD80/CD28)
After activation and clonal expansion under the influence of factors such as IL-2, T lymphocytes perform different functions:
Induce CD8-positive T cell-mediated cytotoxicity (cell lysis and apoptosis induction)
CD4+ T cells provide help for B-cell antibody production, and for macrophages to induce delayed-type hypersensitivity (DTH) responses.
Antigen-specific activation of T cells leads to production of cytokines and chemokines which can activate the natural immune system.
Studies have also provided a link between MHC allopeptide-primed T cells and the development of acute vascular-type rejection mediated in part by accelerated alloantibody production
Accordingly, we can say T cell activation is the cornerstone of alloreactive responses in organ transplantation.
(KEY POINTS
• Acute allograft rejection is likely mediated by indirect and direct pathway CD4 T cell alloresponses.
• Chronic allograft rejection is largely mediated by indirect pathway CD4 T cell responses. Direct pathway recognition of cross-dressed endothelial derived MHC class II alloantigen may also contribute to chronic rejection, but the extent of this contribution is unknown.
• Late indirect pathway CD4 T cell responses will be composed of heterogeneous
populations of allopeptide specific T helper cell subsets that recognize different alloantigens and are at various stages of effector and memory differentiation.
• Knowledge of the precise indirect pathway CD4 T cell responses active at late time
points in a particular individual will likely inform the development of alloantigen-specific cellular therapies and will guide immunometabolic modulation.)
Siu JHY, Surendrakumar V, Richards JA, Pettigrew GJ. T cell Allorecognition Pathways in Solid Organ Transplantation. Front Immunol 2018; 9:2548.
T cell is the main initiator of immune response, Immune response to a graft occurs in the following 5 steps :
1- Antigen source
Immune response to a graft is either Alloantigen-dependent or alloantigen-independent (tissue injury such as ischemic injury leading to upregulation of expression of adhesion molecules, or shedding of intact HLA )
2- Allorecognition
TCRs recognize antigen peptide complexed with MHC class I or II on the surfaces of APCs (TCR- AG- peptide-APC)
APC is either of the donor (interstitial denderitic cells, vascular endothelium) and this is called the direct pathway (1) and is responsible for acute early graft rejection or of the recipient and this is called indirect pathway and is responsible for chronic graft rejection (2)
3- Costimulation
One or more TCR antigens (CD28, CTLA-4) interacts with its specific legend in APC (B7-1, B7-2). this is called costimulation, CD28 stimulate, while CTLA-4 suppress T cells (3)
4- Activation of T cells, promotion of differentiation
Once costimulation occur, T cells secrete IL2 which activate T cells and promote differentiation into :
A- CD4 positive T cells if APC express HLA class II :
Activate macrophage leading to delayed type hypersensitivity
Provide help to B cells for production of antibodies
B- CD8-positive T cells if APC express HLA type I
It produce cell-mediated cytotoxicity by either killing of the cell or induction of apoptosis
5- Damage of the graft induced by :
CD 8- positive cytotoxicity
Recruitment and activation of macrophage
B cell activation and production of antibodies that produce complement medicated or non complement medicated reaction
REFERANCES
1. Matzinger P, Bevan MJ. Hypothesis: why do so many lymphocytes respond to major histocompatibility antigens? Cell Immunol 1977; 29:1.
2. Vella J, Knoflach A, Waaga A, Sayegh M. T cell mediated immune responses in chronic allograft rejection: Role of indirect allorecognition and costimulatory pathways. Graft 1998; 1:S11.
3. Durrbach A, Francois H, Jacquet A, et al. Co-signals in organ transplantation. Curr Opin Organ Transplant 2010; 15:474.
Excellent summary An updated References list would add a lot
Ban Mezher
3 years ago
T cells activation is the main step in activation of immune response. Once the T cells recognize the donor Ag, it will differentiate into cytotoxic (directly kill the foreign Ag) & helper ( help other immune cells through membrane receptors & cytokine production) lymphocytes.
Also helper T cells can induce B lymphocytes to produce antibodies against graft.
Normally T cells compromised 0.01-0.1% of total lymphocytes but after transplantation it increased to 2-10% of total lymphocytes. This increase in number of T cells after transplantation is explained by :
presence of TCR on T cell membrane which can recognize the foreign antigen through direct( TCR recognize donor HLA as foreign) pathway or indirect (TCR recognize the processed HLA by APC) pathway.
presence of memory T cells which had very high frequency & high proliferation capacity
T cells need 3 steps or signals to complete their full maturation & differentiation :
Signal I: the activation of T cells will be through CD3 complex in association with TCR
Signal II: in this step the T cell complete their differentiation into effector lymphocytes. It occur through co stimulatory receptors on T cells that ligand on APC.
Signal III: involve the production of cytokines BY APC or T lymphocytes.
References:
Handbook of Transplantation. Gabriel M. Danovitch. 6th ed.
Dear All
Treg play an important role in induction of tolerance.
There are 5 subtypes of Treg : natural Treg( nTreg), inducible Treg( iTreg), IL-10 producing type I( TrI, CD8+ Treg, and IL-17 producing Treg.
nTreg form 5-10% of total peripheral T cells & it is stable population can maintain peripheral tolerance & prevent autoimmunity while iTreg can loss its expression of Foxp3 during withdrawal of TGF-B so retain cell phenotype similar to conventional CD4Tcells.
ATG, Alemtuzumab & mTOR inhibitor all can potentiate the tolerance function of Treg.
subtypes of Treg
Number of lymphocytes with regulatory function are present;
regulatory B cells, IL-10+ Foxp3− regulatory CD4+ T cells (Tr1), regulatory CD8+ T cells, and
Foxp3+ regulatory CD4+ T cells which play major role in maintaining immune homeostasis and graft tolerance so preservation of Treg function will be a key to successfull ong-term graft survival without rejection episodes
three Treg subsets have been described in mice and humans: central Treg (cTreg; also referred to as naïve-like or resting Treg), effector Treg (eTreg; also referred to as activated Treg), and memory Treg (mTreg.
T reg cells are subtype of T lymphocytes
It expresses CD4, CD25, and FOXP3 on it surfce it is major player in the immune tolerance .
Tregs comprise 5–10% of peripheral CD4+ T cells in the circulation.
And it can suppress different types of T cells initially known to suppress CD4+CD25− T cells Recently, Tregs have been implicated in the regulation of other cells in adaptive immune system including CD8+ T cells and B cells .
Tregs also regulate the function of cells of the innate immune system like macrophages, dendritic cells, and neutrophils .
Another type of Treg cells is called IL-10-producing T regulatory type 1 (Tr1) cells they usually do not express FOXP3 and have been shown to have strong suppressive ability .
Tr1 cells are able to inhibit CD4+ T cell responses through IL-10 dependent and independent mechanisms .
Importantly, Tr1 cells are distinct from FOXP3+ Tregs (natural Tregs) because they do not constitutively express FOXP3. Also, Tr1 cells have been shown to function separately from FOXP3+ Tregs in certain conditions.
Grazia Roncarolo M, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev. (2006) 212:28–50.
Vieira PL, Christensen JR, Minaee S, O’Neill EJ, Barrat FJ, Boonstra A, et al. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol. (2004) 172:5986–93.
O’Garra A, Vieira PL, Vieira P, Goldfeld AE. IL-10-producing and naturally occurring CD4+ Tregs: limiting collateral damage. J Clin Invest. (2004) 114:1372–8.
What are the immunosuprressive medications that potentiate the tolerance function of Treg?
The immunosuppressive drugs from the mTOR inhibitor class (i.e. rapamycin and everolimus) bind to FKBP12 (FK506 binding protein 12) and suppresses mTORc1.
rapamycin was shown to maintain or to promote human Treg expansion and function.
rapamycin also stabilized Foxp3 transcripts and prolonged half-life of adoptively transferred Tregs in rhesus macaques, compared to no treatment .
Among immunosuppressive drugs, rapamycin stands out as having the most benefits in sparing or promoting Tregs in PBL of transplanted patients. Indeed, kidney transplant patients on rapamycin as a maintenance therapy at 1 year post-transplantation had significantly higher fractions of Tregs in PBL compared to patients on calcineurin inhibitors (CNI) 1.
conversion from CNI to rapamycin or to mycophenolate mofetil (MMF) increased the numbers and fraction of Tregs in PBL 2.
CD28 co-stimulation blockade using belatacept or CNI reduces IL-2 levels and adversely affects Tregs. Low-dose IL-2 might be combined with these immunosuppressive drugs to counteract this deleterious effect on Tregs, as previously demonstrated 3.
Reference
1 Segundo DS, Ruiz JC, Izquierdo M, et al. Calcineurin inhibitors, but not rapamycin, reduce percentages of CD4+CD25+FOXP3+ regulatory T cells in renal transplant recipients. Transplantation 2006; 82: 550– 557.
2 Gallon L, Traitanon O, Sustento-Reodica N, et al. Cellular and molecular immune profiles in renal transplant recipients after conversion from tacrolimus to sirolimus. Kidney Int 2015; 87: 828–838.
3 Zeiser R, Nguyen VH, Beilhack A, et al. Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood 2006; 108: 390–399.
Thanks Shereen
Subsets of TREG CELLS
1- Natural Treg cells express CD25 and has special transcription factor Fox3p which is responsible for their activation toward immune tolerance.
2- Tr1 regulatory cells which is cytokine synthesis producing factor as it secrete IL-10 which inhibit inflammatory cytokine production and modulate APCs and act toward immune tolerance. It also secrete TGF-β which add to immune tolerance.
3- Th3 regulatory cells it induce immune suppression following ingestion of an antigen ( oral immune tolerance). It secrete TGF-β and help in IgA secretion.
4- CD8 regulatory cells
5- NK regulatory cells recognize antigens that express CD1d molecule.
ATG deplete absolute lymphocytic count , but affect T cell conventional count more than Treg count, Treg also can be renewed faster than conventional count.
AntiCD25 monoclonal antibodies like basiliximab and dacluzimab they affects Treg uncertainly, they affect modulation of CD25 expression on Treg without affecting number but this effect is transient.
Anti CD52 monoclonal antibody alemtuzumab…CAMPATH-1H help immune tolerance as it deplete conventional T cells more than Treg so the number of Treg increase relative to conventional T cells , also increase anti-inflammatory cytokines like IL-10, IL-4, TGF-β, and decrease inflammatory cytokines as IL-17 and INF gamma.
CNI cyclosporine and tacrolimus affect negatively on Treg as they decrease Fox3p expression , and decrease IL-2 which is regulator of Treg proliferation.
MMF help in Treg homeostasis and function, it increase Treg over Th17.
Steroid therapy methylprednisolone alters T cell composition to favorable Treg cells , also can facilitate Fox3p expression and TGF-β signaling.
mTor inhibitors increase Treg cells proliferation in comparison to cyclosporine, unfortunately, this has no change of graft loss, neoplasm development and rejection episodes.
CTLA4-Ig as balatacept and abatacept both inhibit CD28 co-stimulation, which decrease effector T cells and promote Treg homeostasis.
Rituximab deplete B cell population , it is unclear now to determine its effect on Treg cells through increase CD4 CD25 Treg population , some studies said it increase Treg and some studies showed no effect.
Akiko Furukawa, Steven A. Wisel, Qizhi Tang. Impact of immune-modulatory drugs on Treg. Transplantation. 2016 Nov; 100(11): 2288–2300.
Maryam Gol-Ara, Farhad Jadidi-Niaragh, Reza Sadria, Gholamreza Azizi, and Abbas Mirshafiey . The Role of Different Subsets of Regulatory T Cells in Immunopathogenesis of Rheumatoid Arthritis. Hindawi. Volume 2012.
Regulatory T cell (TREG): these cells are the major regulators of the immune response. They can be distinguished from other T cells by the expression of high levels of CD25 and the transcription factor FOXP3. “Natural” TREG comes directly from the thymus, and helps maintain self-tolerance. They are subpopulations of T lymphocytes defined by the expression of CD4+ and CD25+ molecules, as well as by the transcription factor FOXP3. Treg cells exhibit high expression of the IL-2α receptor (CD25) and low expression of CD127.
With the use of Treg cells in the therapy of human diseases, it is important to distinguish between cell subtypes. Expression in the Helios molecule can be effective in differentiating between the subtypes of tTreg and iTreg/pTreg. Helios is expressed in the thymus, so it may be a marker to identify tTreg from the other populations of Treg, and it acts as upregulation in FOXP3 protein. Cells have super-expression of Helios has a superior effect of peripheral immunosuppression.
Treg-cell therapyThe concept of cellular immunotherapy with Treg is to give the patient Treg cells to decrease the exaggerated immune response in organ transplants. In vivo, low-dose IL-2 treatment increases Treg expansion and is used in the treatment of graft versus host disease (GVHD) and hepatitis C virus-induced cryoglobulinemic vasculitis and, together with rapamycin. Some authors suggest the use of rapamycin for Treg expansion in vivo with an approximately 75–80% yield of pure cells and total depletion of CD8 and CD19.
Three categories of GMP-grade clinical Treg can define: first generation (CD4+CD25+); second generation, bone fide Treg (CD4+CD25+CD127low/−) and third generation naive Treg (CD4+CD25+CD127low/−CD45Ra+). These three types of Treg can be isolated and expanded by Il-2.
Reference:
Cadiele Oliana Reichert, Joel da Cunha, Débora Levy, Luciana Morganti Ferreira Maselli, Sérgio Paulo Bydlowski and Celso Spada (July 12th 2017). Regulatory T Lymphocytes (Treg): Modulation and Clinical Application, Lymphocyte Updates – Cancer, Autoimmunity and Infection, Gheorghita Isvoranu, IntechOpen, DOI: 10.5772/intechopen.69152. Available from: https://www.intechopen.com/chapters/55657
Do you think that all subtypes of Treg have the same potential in induction of tolerance (you have to classify the Treg first)
Five subsets of Tregs had been identified:
nTregs ( natural), iTregs ( peripheral), Tr1 cells, CD8+ Tregs, IL-17-producing FOXP3+ Tregs. Each of them seems to play different role in controlling immune system. Naturally occurring Tregs express their suppressive effect through cell contact by membrane bound molecules, while Tr1 is contact dependent and is based mainly on cytokines such as IL-10, TGF-beta.
References:
What are the immunosuppressive medications that potentiate the tolerance function of Treg?
steroids, mTORi, MMF, efalizumab( Anti LFA-1i), Tocilizumab ( Anti IL-6 ab), Anti CD28 ab, TNFi, CTLA4 Ig.
Reference:
Furukawa A.,Wisel S.A., Tang Q. Impact of immune-modulatory drugs on Treg. Transplantation. 2016 November ; 100(11): 2288–2300.
There are several types of T reg as CD4+ T reg expressing FOXP3, CD8+ T reg cells , and IL 10 producing T reg cells type 1.
The major role of T reg cells in tolerance is played by CD4+ T reg cells expressing FOXP3,CD25, and alpha chain of IL2 receptor.
The effect of immunosuppressive drugs on T cells is through the balance between suppression of effector T cells and activation of T reg cells. Some immunosuppressive drugs are friendly with T reg cells such as ATG, anti CD52, MMF and mTOR.
Ref:
Impact of immune-modulatory drugs on Treg (nih.gov)
Sub types of Treg cells: Natural Treg cells, induced Treg cells, memory Treg cell, and other sub types of Treg cells that are illustrated in attached figure. Activated memory Tregs arise from thymic-derived natural Tregs or peripherally induced Tregs. A functional specialization of Tregs has been described. Tregs can express distinct transcription factors, chemokine receptor to specifically inhibit TH1, TH2, TH17, or TFH responses.
An increase in circulating HLA-DR+ mTregs is associated with better outcome in stable recipients.
Some studies have demonstrated enhancement of Treg function using clinically relevant doses of CNIs.
Inhibitors of the mTOR pathway are well-established pro-Treg factors, and can increase and stabilize Treg phenotype
T reg are subdivided according to expression of CD25,FOXP3 and CD45RA in to 3 populations 1
1- Population 1:naïve Treg FOXP3+CD45RA+CD25++
2- Population 11:effecr T reg FOXP3hiCD45RA–CD25+++,, most suppressive one ,derived from 1,short life span
3- Population 111:memory Treg FOXP3+CD45RA–CD25++,no information about its role
They can be divided according to the origin to2
1- nTREG (natural)cells from thymus
2- iTREG(induced regulatory) cells, peripherally generated from t effector cells
They can be divided according to the level of FOXP3 expression and the isoform of CD45 ,2
1- Resting CD45ra+FoXP3low;
2- 2- CD45ra–FoXP3high
3- the CD45ro+FoXP3low: is not suppressant. It had effector activity since they produce cytokines
The resting can get CD45ra–FoXP3 high phenotype once activated and both of them are suppressive
1- Edozie, Francis C.1,2; Nova-Lamperti, Estefania A.1,2; Povoleri, Giovanni A.M.1,2; Scottà, Cristiano1,2; John, Susan2,3; Lombardi, Giovanna1,2; Afzali, Behdad1,2,4 Regulatory T-Cell Therapy in the Induction of Transplant Tolerance, Transplantation: August 27, 2014 – Volume 98 – Issue 4 – p 370-379 doi: 10.1097/TP.0000000000000243.
2- Li XC, Turka LA. An update on regulatory T cells in transplant tolerance and rejection. Nat Rev Nephrol. 2010 Oct;6(10):577-83. doi: 10.1038/nrneph.2010.101. Epub 2010 Aug 3. PMID: 20683480.
Treg help to maintain graft tolerance and graft acceptance Tregare CD4+cells that Express high level of IL-2 receptor CD25 along with transcription factor FOXP3.main 2 types of Treg are Treg natural that derived from thymus and peripheral inducible which are induced either from natural Treg or naiveCD4+CD25- cells ,main idea of using Treg in tolerance is how to expand their number either endogenous or by infusion exogenously.
Alot of immunosuppressant used to increase Treg activation and maintenance like ATG ,anti IL-2 receptors Ab and anti CD52 Ab all potentiate Treg expansion also mTOR inhibitors promote Treg survival and function .
The regulatory T cells , formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens,andprevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells.Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Recent research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.
Four sub types :-
natural Treg( nTreg),
inducible Treg( iTreg),
IL-10 producing type I( TrI, CD8).
IL-17 producing Treg.
Medications , ?
steroids,mmf
, mTORi,
Tocilizumab ( Anti IL-6 ab),
Anti CD28 ab,
T cell is the main player in transplant immunology it is responsible for acute cell mediated rejection through direct pathway of recognition of transplanted HLA by recipient T cells
APCs present foreign peptides to recipient cytotoxic CD8 leading to the cell activation
T cell also responsible for chronic graft damage through indirect pathway in which donor cells engulf it by recipient APCS & presented to recipient CD for and helper t cell
T cell also release cytokines which activities B cells and antibody Mediated rejection
T reg cells inhibit potentially harmful effects of Th cells, through inhibiting cell proliferation ,cytokine production thus preventing autoimmunity and suppressing allo immune responses.
Naturally occurring T reg produce their effect through cell contact by membrane bounding molecules but Tr 1 effect is related to IL-10.
T reg effects are enhanced by steroids ,mTor i ,MMF ,eflizumab and toclizumab.
References;
Handbook of Kidney Transplantation ,Danovitch,G, Sixth edition
Furnkaw,A,et al : Impact of immune modulating drugs on Treg,Transplantation,2016,Nov,100(11):2288-2300
t cells responsible for innate immunity (cellular immunity)and also activation of b cells that produce plasma cells and then immunoglobulins so T cells responsible for both cellular and humoral immunity
CD8 T cells:
Recognize antigenic peptides presented on MHC class I
They have direct cytotoxicity to target cells they can secrete cytokines
CD4 T cells:
Recognize antigenic peptides presented by MHC class II molecules presented by APC . They play a role in cellular rejection and antibody mediated rejection, provide help to CD8+ T cells so help graft directed cell response as well as having an important role in HLA specific antibody formation via B cell activation and IgM to IgG isotype switching.
Memory T cells:
They may be present due to prior allogenic exposure ,they can be activated without co-stimulation.
T regulatory cells:
Treg suppress the function of different cells as CD4+, CD8+ T cells, macrophages, dendritic cells, NK cells & B cells . They include subclass natural treg,tr1,th3,Cd8treg and NKreg which plays important role in tolerance and used as cellular immune therapy.
The ability of the immune system to differentiate self from nonself is critical in determining the immune response to antigens expressed on transplanted tissue. Even with conventional immunosuppression, acceptance of the allograft is an active process often determined by the presence of regulatory T cells (Tregs). Tregs classically are CD4+ cells that constitutively express high levels of the IL-2 receptor α chain CD25, along with the transcription factor Foxp3. The use of Tregs in the field of solid organ transplantation is related specifically to the objective of achieving tolerance, with the goal of reducing or eliminating immunosuppressive drugs as well as maintaining tissue repair and managing acute rejection. A key issue in clinical use of Tregs is how to effectively expand the number of Tregs, either through increasing numbers of endogenous Tregs or by the direct infusion of exogenously expanded Tregs. In order to realize the benefits of Treg therapy in solid organ transplantation, a number of outstanding challenges need to be overcome, including assuring an effective expansion of Tregs, improving long-term Treg stability and reduction of risk-related to off-target, nonspecific, immunosuppressive effects related specially to cancer.
***Transplant tolerance has been defined as maintenance of stable allograft function in the absence of immunosup- pressive therapy
The role of regulatory T cells (Treg) in the generation and maintenance of immune tolerance is an attractive yet elusive one
Tregs are defined as those anergic and hyporesponsive to stimulation of T-cell receptor (TCR) with suppressive action on the proliferation and activation of helper CD4+ T cells and cytotoxic CD8+ T cells via cell-to-cell contact. Tregs with their Foxp3-expressing marker are strongly suppressive of proliferation of effector T cells and memory T cells, thus controlling excess immune response to foreign antigens, and maintain self-tolerance.
***Two major subsets of Tregs have been defined based on their developmental origin: (1) thymus-derived natural Tregs (nTregs), characterized by constitutive Foxp3 expression, and (2) peripheral induced Tregs (iTregs), where Foxp3 expression seems unstable [14]. Although both T-cell subsets possess regulatory properties, they differ in their developmental pathways, TCR repertoires, and activation requirements. nTregs develop within the thymic medulla, around Hassall’s corpuscles, under the effect of both IL-2 and transforming growth factor (TGF)-β . The other crucial step for Treg development is the engagement of TCRs with MHCII molecules loaded with self-peptides. After exiting the thymus, nTregs form 5–10% of the total peripheral T cells. Their presence in the periphery as a stable population of T cells
Tregs for Transplant Tolerance contributes to the maintenance of peripheral tolerance and prevents the development of autoimmunity .In contrast, iTregs develop in the periphery under the influ- ence of different cytokines as an adaptive immune response. A milieu rich in IL-2 and TGF-β appears to polar- ize the naïve T cells towards iTregs . This makes iTregs display more flexible biomarker features with the capacity to transform into different T-cell subtypes depending on the prevailing cytokine milieu . Clinical trials have shown that iTregs generated in vitro are com- parable to nTregs in immunoregulatory activity. How- ever, withdrawal of the TGF-β from iTreg cultures will result in rapid loss of Foxp3 expression, along with a re- version to a cell phenotype akin to conventional CD4+ T cells [18]. In stark contrast, Foxp3 expression by nTregs is independent of TGF-β, as evidenced by the normal amount and function of nTregs in TGF-β-deficient mice.
***Tregs have been used experimentally to explore treatment of other auto- immune disease conditions, such as colitis, lupus, diabetes mellitus, and glomerulonephritis. The first proof-of- concept clinical trial of polyclonal adaptive Treg transfer to treat graft-versus-host disease turned out to be promising . A major limitation of polyclonal Tregs is the low abundance of the specific clones of interest within the polyclonal repertoire. While antigen-specific Tregs would be superior, their isolation and expansion are still chal- lenging. Recently, Trivedi et al. conducted a clinical trial on a group of live-donor renal transplantation patients using pretransplant stem cell transplantation. The Tregs for Transplant Tolerance patients achieved successful withdrawal of the immunosuppressants with low-dose daily steroid monotherapy. They concluded that generation of peripheral Tregs was necessary to maintain tolerance and that the survival and presence of Tregs is important to protect the graft from chronic rejection.
References:
1-Halloran PF: Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004; 351:2715–2729. Kidney Dis 2018;4:205–213 DOI: 10.1159/000490703
2-Scandling JD, Busque S, Shizuru JA, Engle- man EG, Strober S: Induced immune toler- ance for kidney transplantation. N Engl J Med 2011;365:1359–1360.
3-Starzl TE: Immunosuppressive therapy and tolerance of organ allografts. N Engl J Med 2008;358:407–411.
4-Roussey-Kesler G, Giral M, Moreau A, Subra JF, Legendre C, Noël C, et al: Clinical opera- tional tolerance after kidney transplantation. Am J Transplant 2006;6:736–746.
* Immunosuppressive potentiate the tolerance function of Treg?
steroids, mTORi, MMF, efalizumab( Anti LFA-1i), Tocilizumab ( Anti IL-6 ab), Anti CD28 ab, TNFi, CTLA4 Ig.
The regulatory T cells , formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are
immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells.Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Recent research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.
Subtypes of TREG :
1-nTregs :
The CD4(+)CD25(+)Foxp3(+) cells, which secret IL-10 and TGF-β, and represent one of the largest subsets of Treg.
2- iTregs :
In contrast to nTregs, iTregs are peripherally induced Tregs. Naive CD4+ T cells in the periphery are induced to express Foxp3 in response to foreign antigens [9] and these cells have suppressive function similar to nTregs [16]. iTregs has considerable significance in preventing asthma if generated early enough in life [4]. In addition, Th3 cells that secrete TGF-β and IL-10 belong to this subset .
3-Tr1 cells :
The CD4+ T cells that do not express Foxp3, but secret IL-10 and suppress effector functions of Th cells are known as Tr1 cells.
4- CD8 + Tregs :
A subset of Tregs expressing CD8 is rapidly generated from OT-1 CD8 cells in the presence of IL-4 and IL-12, produce IL-10, and exhibits a unique cell-surface phenotype with coexpression of activation and naive cell-associated markers. They are also observed in tonsils, but rarely detected in peripheral blood. IL-17-producing Foxp3+ Tregs.
It is reported that human peripheral blood and lymphoid tissue, but not thymus contain a significant number of CD4(+)Foxp3(+) T cells that express CCR6 and have the capacity to produce IL-17 upon activation. These cells coexpress Foxp3 and RORgammat transcription factors. The CCR6(+)IL-17-producing Foxp3+ Tregs strongly inhibit the proliferation of CD4(+) responder T cells. Human CCR6(+) IL-17-producing Foxp3+ Tregs are differentiated from the CD4(+)Foxp3(+)CCR6(-) Tregs upon T-cell receptor stimulation in the presence of IL-1beta, IL-2, IL-21, IL-23, and human serum
References:
1- Warner JO, Kaliner MA, Crisci CD, Del Giacco S, Frew AJ, Liu GH, Maspero J, Moon HB, Nakagawa T, Potter PC, Rosenwasser LJ, Singh AB, Valovirta E, Van Cauwenberge P. World Allergy Organization Specialty and Training Council. Allergy practice worldwide: a report by the World Allergy Organization Specialty and Training Council. Int Arch Allergy Immunol. 2006;139(2):166–174. doi: 10.1159/000090502.
2-Barnes PJ. Pathophysiology of allergic inflammation. Immunol Rev. 2011;242(1):31–50. doi: 10.1111/j.1600-065X.2011.01020.x.
3/ Afzali B, Lombardi G, Lechler RI, Lord GM. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol. 2007;148(1):32–46. doi: 10.1111/j.1365-2249.2007.03356.x.
1- Naturally occurring CD4+CD25+ Tregs developed from CD4+T cell precursors directly, under the influence of medium avidity interactions with thymic epithelial cells.
o the conventional CD4+CD25-T cells express FoxP3, which conferred suppressor function of the T cell subset.
o Activated T cells express CD25, GITR, OX40, L-selectin, CTLA-4 ( all these markers are useful for phenotyping identification of naturally occurring CD4+CD25+
2- Induced Tregs develop from naïve conventional CD4+T cells by either:
o Cell contact-dependent interaction with naturally occurring CD4+CD25+ Tregs.
o Under the influence of suppressive agents like IL-10, TGF-B, vit D3, Dexamethasone and other inhibitory mechanisms.
Reference:
1. Jonuleit H, Schmitt E. The Regulatory T Cell Family: Distinct Subsets and their Interrelations. J Immunol [Internet]. 2003 Dec 15;171(12):6323 LP – 6327. Available from: http://www.jimmunol.org/content/171/12/6323.abstract
Transplantation is unusual in that T cells can recognize alloantigen by at least two distinct pathways: as intact MHC alloantigen on the surface of donor cells via the direct pathway; and as self-restricted processed alloantigen via the indirect pathway. Direct pathway responses are viewed as strong but short-lived and hence responsible for acute rejection, whereas indirect pathway responses are typically thought to be much longer lasting and mediate the progression of chronic rejection. However, this is based on surprisingly scant experimental evidence, and the recent demonstration that MHC alloantigen can be re-presented intact on recipient dendritic cells—the semi-direct pathway—suggests that the conventional view may be an oversimplification.
●Direct pathway :
CD4 T cell responses are limited to the first few weeks after transplantation
“direct” pathway activation is largely due to recognition of intact alloantigen acquired onto the surface of host APCs by transfer of donor-derived extracellular vesicles.
●in direct pathway .
CD4 T cell responses against self-restricted processed alloantigen can last much longer than those against intact alloantigen. functional role for the indirect pathway CD4 T cell response in the progression of chronic allograft
● semi direct pathway.
semi-direct allorecognition is a means by which recipient T cells may recognize “intact” alloantigen. This will result in activation of the same T cell clones as would respond via direct pathway allorecognition. In contrast, those T cell clones responding to the processed alloantigen via the indirect pathway are likely to be very different.
●Reference :
. Lakkis FG, Li XC. Innate allorecognition by monocytic cells and its role in graft rejection. Am J Transplant. (2017) 18:289–92. doi: 10.1111/ajt.14436
PubMed Abstract | CrossRef Full Text | Google Scholar
2. Oberbarnscheidt MH, Zeng Q, Li Q, Dai H, Williams AL, Shlomchik WD, et al. Non-self recognition by monocytes initiates allograft rejection. J Clin Invest. (2014) 124:3579–89. doi: 10.1172/JCI74370
PubMed Abstract | CrossRef Full Text | Google Scholar
T cells become activated through:
Direct pathway:
interaction of their T cell receptors with intact allogeneic MHC molecules on donor cells
and/or donor.
Indirect pathway:
MHC peptides presented by self-MHC molecules on recipient antigen-presenting cells
(APCs) .
Semi-direct pathway:
In addition, recent studies show that alloreactive T cells can also be stimulated through
recognition of allogeneic MHC molecules displayed on recipient APCs (MHC cross-
dressing) after their transfer via cell–cell contact or through extracellular vesicles(1).
T Cell Allorecognition and Rejection of Vascularized Solid Organ Transplants:
Early acute rejection of kidney allografts is essentially initiated by CD4+ T cells
recognizing donor MHC class II molecules in a direct fashion.
This is associated with a rapid trafficking of graft DCs to the host spleen presumably
occurring via reverse trans endothelial vascular migration .
, some studies suggest that these allografts could be rapidly infiltrated with recipient
endogenous alloreactive effector memory T cells.
these memory T cells account for resistance to allograft tolerance induction .
Therefore, primarily naïve and presumably endogenous memory T cells activated in a
direct fashion mediate early acute rejection of solid organ transplants.
Suppression of this response by calcineurin inhibitors and other immunosuppressive
agents is regularly achieved in transplanted patients, thereby allowing large-scale
There is strong circumstantial evidence suggesting that T cells activated indirectly are
responsible for chronic allograft rejection.(2).
Reference:
1- Jose Marino, Joshua Paster and Gilles Benichou by T
Lymphocytes and Allograft Rejection. Immunol.14 December 2016
Impact of approved immunosuppressive drugs on Treg
Anti-thymocyte globulin
• rATG is a polyclonal preparation from rabbits immunized with human thymocytes that depletes CD4+ and CD8+ T cells with CD8+ T cells recovering more rapidly and completely than CD4+ T cells.
• ATG mediated immunosuppression induces apoptosis and induction of T-cell anergy at low doses, antibody-dependent cellular cytotoxicity at moderate doses, and complement-mediated lymphocyte lysis at high doses
• Treatment of human peripheral blood lymphocytes with low-dose ATG induces expression of CD25 and FOXP3 in CD4+CD25− cells
• ATG induction therapy reduces the absolute number of Treg, but less than that for Tconvs, altering the Treg/Tconv ratio.
• Treg recover faster during immune reconstitution following ATG treatment, contributing to the sustained elevation of Treg/Tconv ratio
• High-dose ATG impairs thymic generation of Tconv and Treg cells in allogeneic hematopoietic stem cell transplantation
• ATG therapy regulate antigen-specific immune responses by inducing memory-like Treg and T cells such as Th2 and IL-10-producing Tr1 cells.
• ATG is not only induces T cell depletion, but also in relative preservation of Treg especially at lower doses.
Anti-CD25 mAb
• basiliximab and daclizumab- block the IL-2-binding site of CD25
• suppress immune response by targeting recently activated effector T cells that express CD25
• inhibit activation of CD25− T cells by blocking CD25+ DCS from transpresentation of IL-2
• In transplant patients, Basiliximab can lead to a transient reduction of both Treg and down-modulation of CD25 expression on Treg without deleting the cells or impairing their functions
• CD25lo Treg are able to increase CD127 expression and IL-7 responsiveness following daclizumab treatment in MS patients that explains Treg rescue in the absence of IL-2 signaling
• Daclizumab able to increase CD56hi NK cells by increasing the bioavailability of IL-2. CD56hi NK cells suppress immune responses by killing autologous activated T cells or allogeneic APCs
• anti-CD25 inhibits effector T cells and effect on Treg appears to be trasient
• Anti-CD25 mAb may promote Treg-independent tolerogenic mechanisms that may offset anti-CD25 mAb impairment of Treg.
Anti-CD52 mAb
• CD52 is highly expressed on T cells and B cells
• ADCC and complement activation via anti-CD52 are likely mechanisms for alemtuzumab-mediated killing of CD52+ cells
• Depletes activated Tconvs over Treg, resulting in a transient elevation of the Treg to Tconv ratio
• induce conversion of Tconv into Treg, increase anti- inflammatory cytokines IL-4, IL-10 and TGF-β, and suppress proinflammatory cytokines IFN-γ and IL-17
CNI
• inhibit the intracellular phosphatase calcineurin, which dephosphorylates cytosolic nuclear factor of activated T cells (NFAT) to allow for its nuclear translocation and transcriptional activation of cytokine genes such as IL-2
• IL-2 is a regulator of proliferation, survival, and maturation for all T cell subtypes, including Treg
• impair Treg by directly inhibiting Treg activation, inhibiting the generation of pTreg, and indirectly by limiting IL-2 production by Tconvs
• NFAT binding to the CNS1 enhancer is important to pTreg induction88 and its binding to CNS2 enhancer is critical for Treg stability
• High-dose CNI exposure alters gene expression in Treg
• Treg are resistant to low-dose CNI and combing CNIs with sirolimus restore Treg suggest that reducing CNI dose may not only spare patients from the nephrotoxicity, but also spare Treg
Mycophenolate
• promotes Treg predominance over Th17 cells by inhibiting T cell Ig mucin-1 expression, a protein that promote differentiation into effector T cells than Treg
• But administration of supra-therapeutic MMF monotherapy to mice receiving Treg cell therapy reduced the efficacy of Treg
• In liver transplant recipients, conversion from CNI to MMF with a 1-time dose of daclizumab showed an increase in the percentage of Treg from baseline
• Analysis of kidney transplant patients on stable immunosuppression regimens identified higher levels of CD4+CD25highFOXP3+ Treg in patients receiving MMF versus everolimus
mTOR Inhibitors
• acts through mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2)
• Th1 and Th17 differentiation of CD4+ T cells are dependent on mTORC1
• Th2 differentiation requires mTORC2
• In kidney transplant recipients, patients on sirolimus maintenance immunosuppression show a 4-fold increase in circulating Treg when compared to patients receiving cyclosporine
• targeting mTOR may promote pTreg induction and selectively suppress Tconvs while sparing Treg. Treg favoring effect is dose-dependent and high doses of mTOR inhibitors will also negatively impact Treg function
References
Furukawa, A., Wisel, S. and Tang, Q., 2016. Impact of Immune-Modulatory Drugs on Regulatory T Cell. Transplantation, 100(11), pp.2288-2300.
T cells are required for allograft rejection. Alloreactive T cells can be found in the naïve and memory T cell populations, but both require recognition of nonself MHC molecules to become activated. Reactions mediated by naïve T cells take longer to develop than those mediated by memory T cells, which can be generated more quickly and with higher numbers of cells (secondary response). During allograft rejection, both populations are activated simultaneously.
CD4 and CD8 Coreceptors T cells fall into two major classes with different effector functions, distinguished by the expression of the cell-surface proteins CD4 and CD8 .
Both CD4 and CD8 have a cytoplasmic tail that can associate with signaling proteins important in T cell activation. CD4 and CD8 binding to MHC are required to make an effective response. Thus these molecules are called coreceptors.
These processes are controlled by cytokines, including IL-2, which acts on the T cell in an autocrine fashion or by paracrine secretion to neighboring T cells. Activated T cells produce the alpha subunit (CD25) of the IL-2 receptor (IL-2R), enabling a fully functional signaling receptor composed of α, β, and γ subunits that can bind IL-2 with high affinity, which in turn initiates another pathway mediated in part through the protein mammalian target of rapamycin (mTOR).
CD4 and CD8 T cells have different roles during immune responses.
CD4 T cells are both effectors and regulators and have heavy cytokine secretion. After prolonged stimulation, CD4 T cells tend to express groups (signatures) of several cytokines, probably depending on the local environment, nature of the antigen, and type and activation status of the APC.
Feehally J. Comprehensive Clinical Nephrology. SIXTH EDITION.2019
There a two subtypes of Tregs:
1- natural Treg (nTreg)are CD4+ CD25+ Foxp3+
2- induced Treg (iTreg) is developed by tolerance
Tregs secret cytokines including TGFβ, IL-10 and IL-35. Tr1 regulatory T cells secret IL-10 and have suppressor function.
Drugs such as mTOR inhibitors potentiate tolerance function of T regulatory. But CNIs have opposite effect on Treg.
T cells have important role in acute and chronic rejection .Effector T cells cause graft damage after recognition of allo-Ags by CD4+ and CD8+ T cells .So first step is allo-recognition which is induced by major or minor histocompatibility complex or antigens (MHC and miH). Ags can be recognized by direct, indirect and semi-direct pathways to recipient TCRs. Some Chemokines and cytokines trigger recruitment of recipient T cells into the graft. Both naive and memory T cells can initiate an immune response. Memory cells have rapid response to prior Ags and are resistant to apoptosis .This kind of rejection is not responding to treatment very good. CD8+ T cells are contributing in rejection, too. They contain perforin, granzyme A and Fas ligand and perform their action by cell killing.
Activation of Tcells is based on three signals. Binding of HLA introducing antigen to Tcell receptor makes signal 1. Signal 2 is co-stimulation through integrins, B7-CD28, CD40-CD154 and other co-stimulatory molecules and signal 3 is made by cytokine roles in proliferation and differentiation of Tcells to effector T lymphocytes.
Question 1;
Question 2 ;
mTORi e.g. Sirolimus or Everolimus are associated with up regulations of Treg and therefore augment the tolerance function of Treg.
T cells are important part of adaptive immunity and it plays key roles in allorecognition, signal transduction. T Cells includes ; CD4,CD8, Regulatory cells, and Memory cells.
T cells interact with B cells, and Macrophages of innate immunity.
Reference ; Oxford hand book of nephrology & hypertension, second edition
TCRs expressed on T lymphocytes membrane
TCRs recognize alloantigens via two pathways
direct and indirect
T lymphocytes activation and prolifereration and differentiation depends on APCs
T lymphocytes activation depend on 3 signals :
Signal 1 /TCR signaling
Signal 2/Co-stimulation
Signal 3/ Cytokines
Types of T lymphocytes :
Cytotoxic T cell
T-helper cells
T regulatory cells
Memory cells
T-lymphocytes subsets :
Th1 lymphocytes
Th2 lymphocytes
Th17 lymphocytes
Tfh lymphocytes
Cytotoxic T lymphocytes
The IS that act on T lymphocytes are :
Steroid
MMF
CNIs
MTOR
Ameluzumab
Reference is Handbook of kidney transplantation by Danovitch
What is the role played by T cells in transplant immunology?
There is two main types of Tcells Cd4(helper) which interact with antigen presented by APC on HLA class 2
Cd8(cytotoxic) which interact with antigen presented on HLA class 1
Lymphocytes are mainly in inactive(Naive) state and active lymphocytes usually not exceed 0.1% but in kidney Transplantation this figure become 2-10%
Naive Cd4Tcell needs antigen recognition to be activated (adaptive) by 3 main pathways
Direct: by donor APC (100folds potent)
indirect:by antigenic part presented by recipient APC
Semidirect: by whole donor HLA presented by recipient APC
After Cd4Tcell recognition it’s activation started by 3signals
Signal 1: connection between TCR Cd4 and antigen presented on APC
signal 2: connection between cd80/86 on APC and Cd28 on t cell
Signal 3: Cd4Tcell proliferation under effect of IL 2on Cd25 and differentiate into effector t cells which includes
Th1: secrets IL2 and interferone gamma and other inflammatory cytokines and aggravated immune system
Th2: secrets IL10 and antiinflammatories cytokines and inhibit immune response
Th17: secrets IL17 and aggravates immune response
Tfh: which introduce antigen to bcell in the 2ry lymphoid organs and starts humoral immune response
Tmemory: which life longer and get activated without signal 2 and resistant to treatment.
Treg: which also includes subclass natural treg,tr1,th3,Cd8treg and NKreg which plays important role in tolerance and used as cellular immune therapy
Also treg affected by immunosuppressant medications as below
Cni decrease number and function of Treg by inhibition of IL2 secretion
ATG depleting both conventional and treg but treg regenerate faster
Alemutzumab affect conventional tcell more than treg and elicit more tolerance.
MTOR,MMF and steroids increase treg expression and activity.
Allorecognition and activation of alloreactive T lymphocytes depend on three pathways,
direct: T cells react directly to antigens presented by donor antigen presenting cells, this response is associated with acute rejection.
indirect pathway: T cells recognize self antigen presenting cells presenting peptides originating from donor MHC antigens
semidirect immune response: intact allogenic HLA/peptide complex transferred from donor cells to recipient cells activate T cells (1)
CD4+ T cells:
recognize antigenic peptides presented by MHC class II molecules presented by APC as dendritic cells, B cells and macrophages.
they can differentiate into other effector cells. (2)
CD8+ T cells:
recognize antigenic peptides presented on MHC class I which present on most cells
exert direct cytotoxicity to target cells
have proinflammatory function as can secrete cytokines (3)
memory T cells:
they may be present due to prior exposure to alloantigen
memory cells can survive in absence of antigens and can be activated without costimulatory molecules
resistant to apoptosis. (4)
T regulatory cells:
Treg suppress the function of different cells as CD4+, CD8+ T cells, macrophages, dendritic cells, NK cells & B cells through contact & non contact dependent mechanisms. (5)
T helper cells:
T helper cells play a role in cellular rejection and antibody mediated rejection, they provide help to CD8+ T cells so help graft directed CD8+ T cell response.(6)
CD4 T helper cells have an important role in HLA specific antibody formation via B cell activation and IgM to IgG isotype switching. (7)
(1) Issa, F., Schiopu, A. and Wood, K.J., 2010. Role of T cells in graft rejection and transplantation tolerance. Expert review of clinical immunology, 6(1), pp.155-169.
(2) DuPage, M. & Bluestone, J. A. Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease. Nat. Rev. Immunol. 16, 149–163 (2016)
(3) Mittrücker, H. W., Visekruna, A. & Huber, M. Heterogeneity in the differentiation and function of CD8+ T cells. Arch. Immunol. Ther. Exp. 62, 449–458 (2014).
(4)Benichou, G., Gonzalez, B., Marino, J., Ayasoufi, K. and Valujskikh, A., 2017. Role of memory T cells in allograft rejection and tolerance. Frontiers in immunology, 8, p.170.
(5) Romano, M., Tung, S.L., Smyth, L.A. and Lombardi, G., 2017. Treg therapy in transplantation: a general overview. Transplant International, 30(8), pp.745-753.
(6) Marino J, Paster J, Benichou G. Allorecognition by T lymphocytes and allograft rejection. Front Immunol (2016) 7:582.
(7) Steele DJ, Laufer TM, Smiley ST, Ando Y, Grusby MJ, Glimcher LH, et al. Two levels of help for B cell alloantibody production. J Exp Med (1996) 183:699–703
T cells are the major components of the immune system that derived from lymphoid progenitor cells then they become highly specialised each with different receptors which are produced by gene rearrangement making them specific to antigens by recognizing short peptide sequences of the Ag .
The specific receptors of T cells TCR give the total T cells ability to response to any Ag.
T cells are responsible of cell mediated immunity also they have effect against intracellular pathogens,tumors and non self cells.
Main types of T cells :
Cytotoxic T cells ;surface expression of CD 8 (CD 8+T cell) and can directly kill cells that express non self Ag .
Helper T cells; surface expression of CD 4 (CD4+T cell) help to activate macrophages and B cells by giving additional signals .
Regulatory T cells ; control the activity of other T cells and they are important and play role in graft tolerance.
Memory T cells; rapidly change to effector cells when re-exposure to Ag .
T cells activation controlled by 3 signals:
Signal 1 is necessary for T cells proliferation and differentiation but not sufficient alone and it’s produced by binding TCR to Ag (HLA peptides-APCs complex)this lead to their activation .
Signal 2 is mandatory for full T cell activation and differentiation to effector cells ,this occurs by co stimulatory receptors CD 28 on T cells with APCs.
Signal 3 achieved by cytokines named interleukin IL which are proteins secreted by APCs or T lymphocytes themselves such as IL -2.
When naïve T lymphocytes are activated after Ag presentation on APCs , they proliferate and differentiate into several effector cells
1- Cytotoxic T cells : they recognise their specific antigen when its presented on MHC Class I molecules
alloreactive T cells can recognize forign MHC Ags when presented by donor APCs followed by activation of CD4 helper or CD8 cytotoxic cells (direct allorecognition pathway)or Forign Ags are processed then present by recipient APCs to recipient CD4 helper T cells through MHC class II , followed by anhancing B lymphocytes activation , proliferation and Ab production with subsequent graft ingury .(1)
2- T-Helper Lymphocytes : they can differniate into several subtypes including Th1, Th2, Th17, TfH cells and regulatory T cells. T helper cells are activated in response to Ag presentation on MHC class II on APCs.
Functions :
a- Each subtypes secretes a different panel of cytokines that can drive the immune response in a specific direction, so these CD4+T helper cells play a vital role in various immunologic processes as activation of cytotoxic T cells and APCs , maturation and differiation of B cells into plasma cells and memory B cells , antibody production by B cells, recruitment of various inflammatory cells PMNs, eosinophils and basophils as well as development of tolerance and suppression of immune responses
b- T reg are essential for identifying self from non self Ags, inducing natural tolerance through controlling alloreactive T cells , tissue repair and restrict cancer initiation .(2)
3- Memory T cells : they are either CD4+ or CD8+ and are important to provide immune system with memory against previously encountered antigens.
Ref
1- Callus, R., Buttigieg, J., Anastasi, A. A., & Halawa, A. (2017). Basic concepts in kidney transplant immunology. British journal of hospital medicine (London, England : 2005), 78(1), 32–37. https://doi.org/10.12968/hmed.2017.78.1.32
2- de Graav, G. N., Dieterich, M., Hesselink, D. A., Boer, K., Clahsen-van Groningen, M. C., Kraaijeveld, R., Litjens, N. H., Bouamar, R., Vanderlocht, J., Tilanus, M., Houba, I., Boonstra, A., Roelen, D. L., Claas, F. H., Betjes, M. G., Weimar, W., & Baan, C. C. (2015). Follicular T helper cells and humora
The role of T-cell in transplanation
T-cells are the centre of the adaptive immune response to transplant organs.
The role of T-cells in transplantation is allorecgnition, so they affect both rejection and tolerance .
T cells reacting directly to alloantigens presented by donor antigen-presenting cells (APCs) mediate the “direct” alloresponse ( acute rejection) .
The indirect alloresponse, in contrast, resembles more typical immune responses in
which T cells recognize self-APCs presenting peptides on self-HLA molecules .
Cross-talk between B cells with immunoglobulin receptors that bind donor HLA molecules and internalize them ,resulting in focused presentation to indirectly alloreactive T cells that recognize peptide from the same allogenic HLA molecules and help antibody production by those B cells (chronic rejection) .
T-cells activation pass through 3 signal ;
1-TCR signaling
2-Co-stimulation
3- cytokines production
T-cells ( regulator) suppress the effector T cells with different antigen specificities and confer tolerance.
Regulatory T-cells are classified into;
-thymus derived Tregs (natural).
– peripheral inducible Tregs .
Inducible Tregs can be generated from natural Treg or naïve (CD4 ,CD25) cells upon T-cells receptor stimulation in the presence of cytokines such as TGF and IL-2 .
CD4 T-reg cells express high level of the IL-2 receptor alpha chain CD25,together with the transcription factor Fox3.
What are the immunosuppressive medications that potentiate the tolerance function of T-reg;
Calcinurin inhibitors decrease T-reg viability and proliferation.
The effects of mycophenolic acid on T-reg appear to be more variable .
Glucocorticoids appear not to affect T-regs.
mTOR inhibitors promote differentiation and expansion of T-reg as well as increase Foxp3expression,although their effect may decline over time .
induction therapy with thymoglobulin shifts the T-reg to T effector.
Basiliximab may have a deleterious effect on T-reg ,due to the high expression of CD25 on T-reg.
Alemtuzumab uses lead to the generation expansion of T-reg.
Because of the importance of the B7:CD28 interaction for maintenance and generation of T-reg ,the use of Co-stimulatory molecule blocker belatacept reduce their number.
There are none immunosuppressive drugs have been shown to increase T-reg population;
-Metformin
– Erythropoietin
Recent studies showed that inducible Treg treatment decrease serum DSA in a murine model ,indicating a potential use in treatment of humoral rejection.
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T cells play an important role in allorecognition through direct way by T cell receptors that recognise the donor HLA protein or by the indirect way where this donor HLA protein processed by Antigen presenting cells of the recipient that later recognised by TCR.
In the indirect activation of T lymphocytes ,the CD4 differentiate into 5 types:
Th1,Th2,Th17,Tfh and the most important Treg.
Treg necessary for preventing autoimmunity because it express high level of IL-2Ralfa.
Treg has four types T reg ,B reg,anergy and exhaustion.
Because Treg express high level of CD25 and transcription factor Foxp3 ,it play the main role that why if it suppressed,the immune tolerance will achieved
So the lymphocytes depleting agent like ATG is best option for immune tolerance.
T -cells populations:
T cells consider the main player in the induction of immune response.
1-Conventional T helper cells (Th) with subsets of cells (Th1, Th2, Th17, TFh ) they control the adaptive immunity by activating other effector cells such as CD8+ cytotoxic T cells, B cells and macrophages.
2-T regulatory cells with suppresser activity potentiate the suppressing of cytotoxic Th Cells and enhance the induction of tolerance. by ensuring self ⁄ non-self-discrimination.
T-cells activations:
Activation of T Cells is antigen dependent, initiated by APC s
It occurs through three signals signal mode
1-signal 1involve the contact of T cell receptor (TCR) -CD3 complex with MHC peptide complex
2- signal 2 through the costimulatory pathway in the presence of CD28which lead to T cell activation and proliferation to T cells, B7-2 (often known as CD80 or CD86) provides the second signal and prevents T cell to go into anergy.
3-signal3(cytokine production): It is a potent signal involving cytokine production mainly IL-2 that result in T lymphocyte maturation and differentiation into multiple effector subsets.
–Tregs) and their role with effector cells to identify the bases of immune tolerance.
Treg-cell activation is antigen-specific like the Th cells activation, but Treg cells suppressive activity Is an antigen-specific fashion.
Treg-specific molecular marker is still lacking, but Treg with foxp3 expressive marker which have both activating and suppressing effect it considers critical factor for Treg function, Treg cells induced by T-GFB Cytokines will lose FOXP3 expression and suppressive activity upon stimulation, Furthermore, based on recent evidence all CD4+, cd8+Tcells may upregulate FOXP3 with acquiring the suppressive effect upon activation so this lead to conclude the suppressive activity of FOXP3 not limited to T regulator cells ,and its true suppressive effect has been challenged .Additional to that the ability to suppress T cells is clearly not an exclusive property of Treg cells. The mechanism of suppression based on a three-partner interaction between the Treg cell, the Th cell to be suppressed, and the antigen presenting cell (APC). It is well established that conventional Th cell subsets suppress each other. In particular the subsets of conventional Th 1, Tfh, Th17).
Regulatory T cells that expressing CD4, CD25, and the FOXP3 expressive marker, are a highly suppressive population and count for 5% to 10% of CD4+ T cells .
Impact of approved immunosuppressive drugs on Treg:
1- Antithyroglobulin (ATG)
Deplete CD4+, CD8 in the first 3 months of induction therapy its action IL2 dependent apoptosis with induction of T CELL anergy at low doses, it act as antibody-dependent cellular cytotoxicity (ADCC) at moderate doses, and complement-mediated lymphocyte lysis at high doses
ATG is not only limited to T cell depletion, but also in relative preservation of Treg
especially at lower doses.
2-CNI, Cyclosporine, tacrolimus
CNI effect on Treg is dose and duration dependent.
CNIs impair Treg by directly inhibiting Treg activation, inhibiting the generation of pTreg,
and indirectly by limiting IL-2 production by Tconvs. Also inhibit Treg proliferation in a
dose-dependent fashion in vitro.
Low dose CNI can protect the patients from nephrotoxicity and spare the Treg cells function.
3-MMF treatment
promotes Treg expression over Th17 cells by inhibiting T cell Ig mucin-1 expression, a protein that promotes differentiation into effector T cells than Treg.most preclinical and -clinical evidence suggests that MMF is compatible with Treg homeostasis and function.
4-CORTICOSTERIODS
glucocorticoids promote Treg through multiple mechanisms, corticosteroids enhance the Treg prevalence and activity also may create a favorable immune environment for Treg through modulation of local cytokines expressive activities.
5-M-TOR inhibitors, also promote the Treg and its also dose dependent
6- Rituximab still need more studies to confirm its impact on Treg
References:
1- A- Gorthy, how do Regulatory T Cells Work? doi: 10.1111/j.1365-3083.2009.02308.
2-Rathore R, Gunawansa N, Sharma A, Halawa A (2017) Current State of Tolerance: The Holy Grail. Arch Clin Nephrol 3(2): 057-063. DOI ,http://dx.doi.org/10.17352/acn.00002 References:
3- Impact of immune-modulatory drugs on Treg
Akiko Furukawa, MD#, Steven A. Wisel, MD#, and Qizhi Tang, PhD
4- Up to date medicine function of T -cells .
5- -Handbook of kidney transplantation, Fifth edition.
T cells represent about 60-70% of all lymphocytes in circulating blood, The role of T cells in transplantation is allorecognition. Allorecognition is the recognition of the donor alloantigen by the recipient T cells.
T cells have T cell receptors (TCR) on their membrane which is able to attach HLA molecule bounded to the antigenic peptide.
Allorecognition is divided into 2 types:
1- Direct allorecognition : the antigenic peptide is presented to T cells of the recipient by the donor APCs.
2- Indirect allorecognition : the donor antigen is presented to T cells by the host APCs.
T cell activation pass through three signals :
1/ Signal 1 is TCR signalling :
Engagement of TCR with the antigenic peptide attached to HLA molecule results in activation of calcineurin pathway and induction of cytokine gene.
2/ Signal 2 is costimulation :
Engagement of CD28 with members of B7 family. Both signal 1 and 2 will lead to initiation of signal 3.
3/ Signal 3 is cytokines production :
Cytokine production and and their interaction with the corresponding receptors will lead to cell division.
Cytokine production leads to differentiation of T cells into several types of effector T cells. CD4+T cells will differentiate into 4 sub types of T helper cells : Th1. Th2, Th17, Th FH and one regulatory subgroup Treg, while CD8+Tcells will differentiate into cytotoxic T cells, Also , cytokines help these effector T cells to be converted to memory T cells.
All these effector T cells produced as a result of T cell activation will participate in allograft rejection (either acute or chronic) so immunosuppressive drugs directed against these 3 signals of activation help in preserving the graft and preventing the rejection.
REF:
Handbook of kidney transplantation (sixth edition)
T cells have a central role in the process of transplantation either in tolerance or rejection by recognition of foreign antigens. T cells have a role in activating and orchestrating the response. The allorecognition can be direct, indirect, or semidirect.
we have cytotoxic T cells that as their name implies kill their target directly after interacting of CD8 presented on them with MHC las I antigens.
T helper cells have wide range of effector functions. the have many subtypes like TH1, TH2, TH17, TfH and regulatory T cells. the have CD4.
After binding to class II MHC with CD4 the become activated and help shape activate the immune response by helping B cells produce antibodies.
Memory T cells provide immune response to previously encountered antigens. he have either CD4 or CD 8.
In short TH1 activate macrophages, TH2 activate eosinophils and mast cells, TH17 enhance neutrophis response, THfH enable B cells to develop into mast cells.
T regulatory cells on the other hand Suppresses other immune cells, particularly CD4+ and CD8+ responses. They use FOXp3 as transcription factor.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490749/
https://teachmephysiology.com/immune-system/cells-immune-system/t-cells/
T cells play central role in transplant Immunology in case of transplant rejection.
Rejection passes through sensitization stage and Effector stage
Sensitization starts with Allorecognition in which T cells recognise foreign donor peptides , through its TCR then it become activated
Recognition occurs either directly through Recognition of MHC bound Donor antigens ,or indirectly through self APCs.
In normal individuals only 0.01 to 0.1 of individual lymphocytes are considered active , which in transplantation this ratio increases to 2-10% . ( which may be attributed to presence of memory T cells )
Naieve T cell requires 3 signals inorder to be activated and converted to Effector T cells :
1. Stimulation in which TCR interact with MHC peptide complex on APCs
2. Co Stimulation in which Co stimulatory molecules interact together ( CD28 on T cells , and CD B7-1 , CD B7-2 on APCs )
3. Cytokine release .
Early acute rejection of kidney allografts is essentially initiated by CD4+ T cells recognizing donor MHC class II molecules in a direct fashion
In addition, some studies suggest that these allografts could be rapidly infiltrated with recipient endogenous alloreactive effector memory T cells
Studies showed that T cells activated indirectly are responsible for chronic allograft rejection, either on their own or through the induction of alloantibody production by B cells .
regulatory T cells (Tregs) play an essential role by suppressing harmful inflammatory responses .
Tregs are CD4+CD25high T lymphocytes expressing FoxP3 , have an important role on inducing tolerance.
1- steroid expand steroid-related IL-2– dependent expansion of Tregs
2- mTOR expand and and increase Foxp3 expression but decrease with time.
3- alemtuzumab increase generation/expansion,
4- mmf variable
Paloma Leticia Martin-Moreno, Sudipta Tripathi and Anil Chandraker, Regulatory T Cells and Kidney Transplantation, CJASN Nov 2018, 13 (11) 1760-1764; DOI: 10.2215/CJN.01750218
Thanks Hinda for your contribution
Please watch the typos (MMF not mmf).
1. Do you think that all subtypes of Treg have the same potential in induction of tolerance (you have to classify the Treg first)
Tregs are CD4+ cells which express high levels of the IL-2 receptor alpha chain CD25, beside the transcription factor Foxp3. There are many subtypes with functional heterogeneity.
Types of Tregs(Phenotypes) : thymus derived (natural) Tregs, or peripheral inducible Tregs. Inducible Tregs can be generated from natural Tregs or naïve CD4+CD25- cells . 1
Several types of Tregs were described: CD4+, CD8+, CD3+,CD4-,CD8-,file:///C:/Users/USER/AppData/Local/Temp/msohtmlclip1/01/clip_image002.gif , and NK T cells . CD4+CD25+Foxp3+ T cells was the most one studied.
Foxp3 importance was due to the fact it correlate with suppression activity , regulate the expression of CTLA-4, GITR, and CD25 on the Treg surface (used for identification of Treg)2
beside the subtypes , other factors which may influence tolerance include the number of cells needed to be infused, the frequency and timing besides the in vivo migration. Some subtypes produce IL-10 and IL-35, which can make other t cells tolerant (“infectious tolerance”)3
1- Paloma Leticia Martin-Moreno, Sudipta Tripathi and Anil Chandraker, Regulatory T Cells and Kidney Transplantation, CJASN Nov 2018, 13 (11) 1760-1764; DOI: 10.2215/CJN.01750218
2- Sacha A. De Serres, Mohamed H. Sayegh, Nader Najafian, Immunosuppressive Drugs and Tregs: A Critical Evaluation! CJASN Oct 2009, 4 (10) 1661-1669; DOI: 10.2215/CJN.03180509
3- Edozie, Francis C.1,2; Nova-Lamperti, Estefania A.1,2; Povoleri, Giovanni A.M.1,2; Scottà, Cristiano1,2; John, Susan2,3; Lombardi, Giovanna1,2; Afzali, Behdad1,2,4 Regulatory T-Cell Therapy in the Induction of Transplant Tolerance, Transplantation: August 27, 2014 – Volume 98 – Issue 4 – p 370-379 doi: 10.1097/TP.0000000000000243
-T lymphocyte is the main player in the rejection .
– naive T cells priming in the secondary lymphoid tissue by the APC s mainly the dendritic cells then the cells will be activated and differentiate to the subsets of T effectors cells which involved in rejection by different pathways direct pathway via cytotoxic T cells activation and indirectly by attracting and activating macrophage and granulocytes
Also they helped the B cells to produce Allo antibodies .
Memory T cells they directly migrate to the graft and generate effectors in place
Allo reactive T memory cells are prevalent in humans and experimental animals who have never received A-graft.
also T memory cells are less susceptible to most immunosuppressive therapy due to the TCR cross reactivity there fore. Further Understanding about the effector T cells and T memory cells interactions and their dynamic behavior and effects in rejection
the use of new technology called 4D multiphotone intravital Micrscopy
To assess in real time the immune response of both the effector and T memory cells by 4D imaging In the living allograft This led to discovery that in acute rejection both the T effector and T memory cells migration is antigen driven immune response and not by chemokine effect and that dendritic cells called passengers leucocytes reach into capillary lumen to capture T cells .
Also the host Dendritic cells Derive from the host monocytes expressed and migrate in to allograft and acquire DC morphology they continuously interact with the captured antigen specific T cells and maintain their activation {survival and proliferation} in the graft and associated with graft rejection .
References
Four-Dimentional Imaging of T cell in kidney transplant rejection ,review , http://www.jasn.org.
AndrewD .Hughes,FadiGLakkis , and MartinH .Oberbarmscheidt
Role played by T cells in transplant immunology:
1.Allorecognition:T cells are central to the process of transplant rejection through allorecognition of foreign antigens.
direct T cell allorecognition; Native T cells located in LNs become activated through recognition of allogeneic MHC molecules displayed on donor passenger leukocytes(dendritic cells (DCs)).
Indirect Allorecognition; allogeneic MHC class I antigens could be presented by self-MHC class I on antigen-presenting cells (APCs) and trigger the activation of some CD8+ cytotoxic T cells in vitro, a phenomenon referred to as cross-presentation.
Semi-Direct Allorecognition :leukocytes exchange molecules, including RNA and proteins, either via cell–cell contact (trogocytosis), nanotubes, or through the release of extracellular vesicles such as exosomes.
2.Alloresponse: allorecognition of foreign antigens leading to T-Cells activation, and the orchestration of an effector response that results in organ damage.
Direct and indirect allorecognition represent distinct mechanisms involving different APCs, T cells, and antigen determinants. Each of these pathways can sufficiently and exclusively lead to acute rejection of fully allogeneic skin allografts.
In certain circumstances, T cells activated directly and indirectly could either cooperate or suppress each other, a process influencing the survival of allografts.
It is plausible that in recipients of MHC class I-disparate allografts, CD4+ T cells activated exclusively through indirect allorecognition provide help [via IL-2 and gamma interferon (γIFN) secretion] for the direct activation of other CD4+ T cells (three-cell cluster model) or the differentiation of CD8+ cytotoxic T cells recognizing donor MHC class I peptides in a direct fashion (four-cell cluster model) . Likewise, in the absence of bone marrow-derived donor professional APCs, T cells recognizing donor MHC class I or II directly on parenchymal cells can receive costimulatory signals via interaction with CD80/86 or CD40 located on recipient professional APCs (activated through indirect presentation to T cells) (trans-costimulation). At the same time, early inflammatory direct alloresponses associated with γIFN and tumor necrosis factor alpha production and subsequent induction of donor MHC class II expression on endothelial cells presumably enhances allo-MHC antigen processing by recipient APCs and indirect activation of T cells. Therefore, the direct and indirect alloresponses can act synergistically to reject an allograft.
3.Induction of tolerance: Long-term transplant acceptance in the absence of immunosuppressive therapy remains the ultimate goal in the field of transplantation and many studies are exploring potential therapies. One promising cellular therapy is the use of regulatory T cells to induce a state of donor-specific tolerance to the transplant.
Role of T lymphocytes in transplantation
recipient T cells recognize the MHC–peptide complex through the T cell receptor (TCR)
A given T lymphocyte, however, expresses a handful of different TCRs on its surface, allowing it to respond to a limited number of antigens. Normally, anywhere between 0.01% and 0.1% or less of an individual‘s T lymphocytes recognize and respond to a given microbial antigen but in the setting of transplantation, approximately 2% to 10% of T lymphocytes react to the mismatched organ. There are two main reasons for the high prevalence (precursor frequency) of alloreactive T lymphocytes. First, TCRs recognize alloantigens via two pathways:
Direct allorecognition refers to the recognition by TCRs of intact donor HLA proteins that are foreign (allogeneic) to the recipient, whereas indirect allorecognition refers to the recognition by TCRs of donor alloantigens (whether HLA or mHA) that are processed by recipient APCs
and presented as small peptides bound to self- (recipient) HLA molecules—the same pathway responsible for presenting microbial antigens.
The second reason for the high frequency and potency of alloreactive T lymphocytes is the conspicuous presence of memory T lymphocytes in the alloreactive T-lymphocyte repertoire of humans. Memory T lymphocytes share the same
antigenic specificity as their naïve precursors but are present in much higher frequency and have a much greater proliferative capacity once activated by antigen.
T cells cause allograft rejection either by eliciting a DTH response or through cytolytic/cytotoxic activity
CD8+ CTLs are the major players in lymphocyte-mediated cytotoxicity, and they predominate the cellular infiltrates in acutely rejecting grafts [41] . CD8+ CTLs are primed and activated by recognition of donor MHC class I molecules primarily on donor APCs, but also on vascular endothelial cells
What is the role played by T cells in transplant immunology?
T cells are lymphocytes that constitute a major component of acquired immunity.
In transplantation T cells orchestrates the cascade of graft allorecognition resulting in either rejection ( Acute or choronic), or tolerance (allograft acceptance)
T cell allorecognition is the Recognition of donor antigens (allogeneic MHC molecules) by recipient T cells (Allospecific T cells, alloreactive T cells, effector)
(1).
alloreactive T cells are stimulated through one of 3 pathways ( pathways of allorecognition):
Direct Allorecognition
Donor dendritic cells (DCs) (passenger leukocytes) that carry Doner specific HLA , migrate through lymphatics to host regional lymph nodes (LNs) and got recognized through Naïve T cells located in these LNs and trigger the activation of CD8+ cytotoxic T cells inducing rapid and acute cellular rejection (2)
Indirect Allorecognitiondonor antigens are taken up and processed by recipient APCs and presented by self-MHC class II to trigger the activation of CD4+ T
Semi-Direct Allorecognition
Doner MHC class I and II molecules are expressed on cell surface of recipient APCs without being processed, this is done through exchange molecules (MHC cross-dressing) between recipient and donor DCs after transplantation either via cell–cell contact (trogocytosis), nanotubes, or through the release of extracellular vesicles such as exosomes Resulting in T cell activation (3).
In certain circumstances, T cells activated directly and indirectly could either cooperate or suppress each other, a process influencing the survival of allografts.
T Cell Allorecognition Pathways in Regulatory Tolerance
Allograft tolerance, defined as long-term survival of allogeneic transplants in the absence of ongoing immunosuppressive drug treatment, can occur via deletion or inhibition of alloreactive T cells.
Among them, regulatory T cells (Tregs) play an essential role by suppressing inflammatory responses . Tregs are CD4+CD25high T lymphocytes expressing FoxP3 transcription factor either constitutively (thymic Tregs or tTregs) or after peripheral recognition of antigens (peripheral Tregs or pTregs) (4). In addition to their role in self-antigen tolerance, both Treg subsets can suppress inflammatory alloreactive T cells in vitro and in vivo..
References
(1) Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol (2003) 3(3):199–210. doi:10.1038/nri1027
(2) Rosenberg AS, Singer A. Cellular basis of skin allograft rejection: an in vivo model of immune-mediated tissue destruction. Annu Rev Immunol (1992) 10:333–58. doi:10.1146/annurev.iy.10.040192.002001
(3) Dolan BP, Gibbs KD Jr, Ostrand-Rosenberg S. Dendritic cells cross-dressed with peptide MHC class I complexes prime CD8+ T cells. J Immunol (2006) 177(9):6018–24. doi:10.4049/jimmunol.177.9.6018
(4) Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell (2008) 133(5):775–87. doi:10.1016/j.cell.2008.05.009
T cells are mainly produced in the thymus and were first recognized as lymphocytes that do not express surface Ig or genes for Ig . The hallmark of a T cell is expression of an antigen-recognizing T cell receptor (TCR).
There are two forms of TCRs, an a- and b-chain TCR (TCRa,b) expressed by 95% of peripheral T cells , and a g- and d-chain TCR (TCRg,d).
TCR, unlike antibody, does not directly bind to unprocessed antigen. TCR recognizes peptides of antigen presented by MHC present on cell membrane.
To activate T cells, antigen-presenting cells (APCs) must first be activated by the antigen and induced to express MHC and costimulatory molecules. APCs are activated by bacterial wall molecules or virus materials, such as double-stranded DNA, that bind to Toll-like receptors,This leads to production of inflammatory mediators, such as TNF-a, IL-1b, and PGE2, which further activate APCs
The majority of peripheral TCRa,b T cells is effector programmed to become soldiers. A minority of peripheral CD41 TCRa,b Τ cells released from the thymus expresses CD25 and FOXP3, and they are professional Tregs or spies. Both effector T cells and Tregs have a vast array of TCR to recognize a broad repertoire of specific antigen.
How is t cell activated?
Signal 1: TCR Signaling,
Binding of antigen (HLA–peptide complex) to the TCR triggers a signaling cascade that leads to Tlymphocyte activation.
Signal 2: Co-Stimulation ,
engagement of co-stimulatory receptors on T lymphocytes by their ligands on APCs
Signal 3: Cytokines,
Cytokines involved in T-lymphocyte activation are proteins secreted by mature APCs or the T lymphocytes themselves. They serve two main purposes in the context of T-lymphocyte activation: they stimulate Tlymphocyte proliferation and induce the differentiation of T lymphocytes into multiple effector subsets that have distinct phenotypes and functions
A-Interleukin-2 (IL-2) is the first T-lymphocyte mitogen to be discovered by virtue of its strong capacity to induce Tlymphocyte proliferation in culture.
IL-2 is produced by antigen-activated T lymphocytes and acts on the same lymphocytes that produce it (autocrine) or on neighboring lymphocytes (paracrine). Naïve T lymphocytes express a low-affinity form of the interleukin-2 receptor.
WHAT ARE THE TYPES OF T LYMPHOCYTES.?
A-Th1 lymphocytes are the prototypical lymphocyte subpopulation responsible for rejection. Their differentiation is driven by IL-12 and interferon-gamma (IFNγ).
B-Th2 lymphocytes are the lymphocyte subset responsible for allergic reactions. They also contribute to allograft rejection.
C-Th17 lymphocytes constitute a subpopulation that is particularly adept at responding to fungal infections.
D-TFH (follicular helper) lymphocytes play a key role in antibody production by providing help to B lymphocyte
E-Cytotoxic T lymphocytes (CTL) bind via their TCRs to target cells expressing nonself MHC–peptide complexes and induce target cell killing by secreting perforin and granzymes
MEMORY T LYMPHOCYTES
A large number of effector lymphocytes are generated during an immune response, but most undergo activation-induced cell death by apoptosis as the response progresses. The few effector lymphocytes that survive give rise to memory T lymphocytes (TM).
Tregs which are responsible for induction of tolerance.
Acute cellular rejection is T cell–mediated and involves CD41 and CD81 T cells.
REFEERENCE
CJASN ePress. Published on April 15, 2015 as doi: 10.2215/CJN.06620714
The presence of memory T cells has been often correlated with poor outcomes in clinical transplantation. In humans, the presence of memory T cells pre-transplantation has been associated with an increased risk for acute rejection of kidney transplants. 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 in heart-transplanted mice, and CD8+ T cell depletion or limiting their trafficking into the graft significantly extends allograft survival.
Early direct contact of circulating memory CD8+ T cells with donor endothelium up-regulates 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 cardiac allografts within hours after reperfusion. Once in the graft parenchyma, these memory CD8+ T cells proliferate extensively, up-regulate the expression of ICOS, and secrete IFNγ in an ICOS-dependent manner.
Reference:
Benichou G, Gonzalez B, Marino J, Ayasoufi K, Valujskikh A. Role of memory T cells in allograft rejection and tolerance. Frontiers in immunology. 2017 Feb 28;8:170.
T lymphocytes plays an important role in transplantation . Naïve T cells can be stimulated either by direct pathway ( through donor antigen presenting cells ) or by indirect pathway ( through recipient APCs) . Once stimulated , it transforms to either :
Cytotoxic T lymphocytes : which can destroy cells harboring the target antigen by by inserting perforins and granzymes into the cells .
Helper T lymphocytes : Which orchestrates the adaptive immune system . These cells can secret cytokines and activates B cells to become plasma cells . Many subtypes of T helper lymphocytes:
TH1 Lymphocytes : secrets interferon and TNFa which can lead to graft damage directly, also it activate macrophages, stimulate Cytotoxic T lymphocytes, stimulate the differentiation of B cells into immunoglobulin producing plasma cells.
TH2 Lymphocytes : secret cytokines Iike IL4, IL5 , IL10 which activates mast cells and basophiles . TH2 can suppress TH1 lymphocytes.
TH17 Lymphocytes : secretes IL17, which leads to attraction of inflammatory cells to the graft.
Tfh Lymphocytes: T follicular helper lymphocytes stimulate B cell to differentiate to plasma cells through CD40- CD40L and produce IL4, IL21.
T regulatory Lymphocytes (Fox3 +): These cells can suppress T helper and T cytotoxic Lymphocytes and can induce tolerance to the graft . It has 2 subtypes :
Thymus (natural) Treg and peripheral inducible Treg.
Regarding drug effect on Treg : CNI reduce Treg population.
mTOR inhibitors increase the population of Treg.
ATG increase Treg T lymphocytes ratio.
Belatacept reduces Treg.
IL2 increase Treg population.
Metformin increases Treg population.
Erythropoietin inhibit T cells but spares Treg.
References :
(1) Handbook of Kidney Transplantation, SIXTH EDITION
(2) Paloma Leticia Martin-Moreno, Sudipta Tripathi, and Anil Chandraker
Regulatory T Cells and Kidney Transplantation
Clin J Am Soc Nephrol 13: 1760–1764, 2018. doi: https://doi.org/10.2215/CJN.01750218
What is the role played by T cells in transplant immunology?
T cells are the backbone of the graft rejection by virtue of their role in allorecognition of antigen with costimulation, leading to their activation and production of inflammatory mediators, causing graft damage.
The 3 different pathways involving allorecognition are: (1)
1) The direct pathway involves the recognition of donor antigen presenting cell (APC) having MHC-peptide complex by the recipient T cell leading to activation of CD4+ and CD8+ T cells. This pathway has important role in the initial period of transplant, leading to early onset acute rejection which is cellular, involving mainly the interstitium and tubules.
2) The indirect pathway involves the recipient APC presenting the donor peptide to recipient CD4+ T cells via MHC class II, interacting with B cells leading to antibody formation. It is responsible for late onset rejection, especially chronic rejection and predominantly vascular damage.
3) The semi-direct pathway involves priming of CD4+ and CD8+ T cells by the donor MHC-peptide complex acquired by the recipient APC through direct cell to cell contact or from exosomes secreted by the donor APC (cross-dressing).
Once allorecognition happens, T cell activation takes place by 3 signals. (2)
Signal 1: Stimulation – The T cell receptor (TCR) on the CD4 and CD8 cell interacts with the antigen on the MHC molecule
Signal 2: Co-stimulation – Interaction between CD28 ( on T cell) and CD80/86 on the APC
Signal 3: Cytokine production – especially IL-2 leads to T cell maturation and differentiation
The immune response involves stimulating both the naive T cell as well as the memory T cells. Memory T cells can survive even in absence of antigen and can be activated without co-stimulation. They are more resistant to apoptosis and rejection caused by them is resistant to treatment with immunosuppressives and lymphocyte depleting agents.
T cells differentiate into a number of subsets, each having unique functions. (3)
CD4+ T cells: give rise to T helper cells and T regulatory cells
CD8+ T cells: give rise to cytotoxic T cells.
T helper cells:
1) Th1: responsible for cell-mediated immunity. It releases gamma interferon and TGF-beta leading to CD8+ cytotoxicity (using perforin/granzyme pathway), macrophage dependent delayed type hypersensitivity and IgG2a synthesis from B cells activating complement lading to rejection. It also has FasL pathway with cytotoxic activity.
2) Th2: responsible for humoral immunity. It releases IL-4, 5,9, 10 and 13, stimulating B cells and eosinophils leading to graft rejection.
3) Th17: release IL-17, 21 and 22 leading to neutrophil recruitment to the rejection site and hence has role in early post transplant period acute rejection.
4) Tfh: Follicular helper T cells help in conversion of activated B lyphocytes to antibody generating plasma cells.
T regulatory cells (Treg): T cells with regulatory or immunosuppressive action. They control immune homeostasis by maintaining immune tolerance against self-antigen. There are multiple mechanisms of action of Treg, including: (4)
a) Contact-independent anti-inflammatory cytokine (IL-10, IL-35 and TGF beta) production, and exosome formation leading to specif gene silencing.
b) Contact dependent suppression through interaction of CTLA4 on T reg with CD80/86 on APC, restricting T cell access to signal 2.
c) Inducing apoptosis using Fas/FasL and Granzyme/perforin pathways.
d) Disruption of metabolic pathways via CD39, causing decreased ATP triggered proinflammatory signals.
The CD8+ T cells are responsible for graft destruction by apoptosis due to cytotoxic activity.
References:
1) Dewolf S, Sykes M. Alloimmune T cells in transplantation. J Clin Invest 2017;127:2473-2481.
2) Priyadarshini B, Greiner DL, Brehm MA. T cell activation and transplantation tolerance. Transplant Rev (Orlando) 2012;26:212-222.
3) Issa F, Schiopu A, Wood KJ. Role of T cells in graft rejection and transplantation tolerance. Expert Rev Clin Immunol 2010;6:155-169.
4) Vaikunthanathan T, Safinia N, Boardman D, et al. Regulatory T cell: tolerance induction in solid organ transplantation. Clin Exp Immunol 2017;189:197-210.
T cells are the backbone of the human adaptive immune response. The develop from hematopoietic stem cell ,migrate to Thymus to continue their antigen independent maturation.
Alloreactive T cells play a central role in transplantation: they are key mediators of rejection, tolerance and GVHD.
T cell activation:
It is the process in which naïve T cell become activated into effector T cell
APC(dendritic cells play a prominent role) is capable to present antigen bound to MHC to naïve CD4 (T-helper) or CD8 (T –cytoxic).
First signal(stimulation signal): The CD4 and CD8 T cells detect the alloantigens expressed on the foreign graft cells through their T-cell receptors. The T cell receptor interacts with the antigen given by MHC molecules
Second signal(Co-stimulation signal): the interaction between co stimulants mainly CD28 on the T cell surface with its APC surface ligands, B7-1 or B7-2 (often known as CD80 or CD86) provides the second signal and prevents T cell to go into anergy.
Third signal( cytokine production):It is a potent signal involving cytokine production mainly IL-2 that result in T lymphocyte maturation and differentiation into multiple effector subsets.
T lymphocytes populations and functions:
CD4 T lymphocytes differentiate into 4 helper subpopulation(TH1,TH2,TH17, Tfh) and one regulatory subpopulation(T reg), while CD8 T lymphocytes differentiate into cytotoxic T lymphocytes that can kill cells by production of perforin and granzymes.
TH1:responsible for graft rejection through production of IFN gamma, TNF alpha these activate macrophages, activate B lymphocytes to produce complement fixing IgG AB and stimulate differentiation of CD8 T cells to cytotoxic T cells
TH2: responsible for allergic reactions and also contribute to allograft ejection though production Of AB that do not fix complement(less potent than TH1)
TH17: produce IL17 that can cause graft rejection by promoting inflammation and formation of tertiary lymphoid tissue at the inflammation site
Tfh (follicular): provide help for activated B lymphocyte to differentiate to AB producing plasma cells plasma cells
Memory T lymphocytes: few effector lymphocytes give rise to memory T cells which have longer life span, wider migration pattern, lower threshold for activation than naïve T cells with a stronger immune response that is partially responsive to co-stimulatory pathways as B7-CD28
Regulatory T cells (Tregs): They are specialized subpopulation of T cells that inhibit T cell proliferation ,cytokine production, preventing autoimmunity and down-regulate the allo-immune response. So simply they are in charge of suppressing potentially deleterious activities of Th cells.
Finally we conclude that the stimulatory activities of T cells need to be counterbalanced by suppressive mechanisms, in order to fine-tune immune responses.
· How do Regulatory T Cells Work?. A Corthay. Scand J Immunol. 2009 Oct; 70(4): 326–336
· Alloimmune T cells in transplantation. Susan DeWolf and Megan Sykes.The Journal of clinical investigations. J Clin Invest. 2017;127(7)
Hand book of kidney transplantation sixth edition
Excellent summary and to the point, thank you.
The immune response to a transplanted organ consists of both cellular (lymphocyte mediated) and humoral (antibody mediated) mechanisms.
T cells are the maestro in the rejection of grafts.
T cells recognize antigen by different pathways
Direct pathway
T cells of the recipient directly recognize intact allo-MHC molecules on the surface of the donor cell.
The transplanted organ carries APCs in the form of interstitial dendritic cells with high density of allo-MHC molecules which can directly stimulate recipient’s T cells.
number of T cells that proliferate on contact with allogeneic donor cells is extraordinarily high as compared with the number of clones that target antigen presented by self-APC. Thus, this pathway is important in acute allorejection.
Indirect pathway
In the indirect pathway, T cells recognize processed alloantigen presented as peptides by self-APCs.
This pathway is involved in chronic allograft vasculopathy.
Semidirect pathway
The recipient antigen-presenting cell acquired intact donor MHC- peptide complexes via cell to cell contact or exomes and present them to the recipient T cell.
rejection consists of the sensitization stage and the effector stage.
Sensitization phase :
Foreign graft cells expresses alloantigens that are recognised by TCRs on the CD4 and CD8 T cells of recipient.
Two signals are needed for recognition of an antigen;
the first is provided by the interaction of the TCR with the antigen presented by MHC molecules,
the second by a costimulatory receptor/ligand interaction on the T cell/APC surface.
One of the most effective costimulatory pathways is the interaction of CD28 on the T cell surface with its APC surface ligands, B7-1 or B7-2 (commonly known as CD80 or CD86, respectively) .
Other costimulatory molecules include the CD40 and its ligand CD40L (CD154).
Also cytotoxic T lymphocyte–associated antigen-4 (CTLA4) also binds to these ligands and provides an inhibitory signal.
Effector stage
Alloantigen-dependent and independent factors contribute to the effector mechanisms.
Initially, injury responses as IRI induce a nonspecific inflammatory response which is not antigen dependent.
Following activation T cells differentiate into multiple effector populations, the effector cells are either CD4+ T helper or CD8+ cytotoxic T cells.
After activation, CD4-positive T cells initiate macrophage-mediated delayed type hypersensitivity (DTH) responses and provide help to B cells for antibody production.
T cells and T cell-derived cytokines such as IL-2 and TNF-α, inducible nitric oxide synthase (iNOS) and growth factors are upregulated early after transplantation also play a role in this process.
The growth factors, including TGF-ß and endothelin causes interstitial fibrosis, and glomerulosclerosis.
CD8-positive T cells is responsible for CMR either directly or by inducing apoptosis.
Prashant Malhotra,Immunology of Transplant Rejection. (2019 )
Could anyone describe the T and B cells crosstalk during an immune response and how this affects the response to immunosuppression!?
recipient APCs process and present donor antigen to CD4 which recognize MHC II on APCs, also activated CD4 will stimulate B cell to produce antibodies to initiate the complement cascade and start the process of inflammation and rejection.
Cross-talk between T & B cells in transplantation is increasingly recognized as being important for alloimmune response. T cells activation of B cells occur through 3 signal pathway, initial B cell activation is driven by alloantigen. Mature B cells can recognize alloantigen through B cell receptor( signal 1). The second signal is costimulation, a cognate interaction between Th cells and B cells gives multiple costimulation signals for B cell activation. After that B cell activation require cytokines for their activation ( signal 3) produced by various T helper cells including Th1, Th2, Th17. In addition Tfh is required for B cells activation.
There are number of drug therapies which can affect T-B cells cross talk including: costimulatory blockade Belatacept, CD40 ligand blockade, Anti LFA1 blockade ( Efalizumab), Belimumab, Atacicept.
Reference:
Kwun J.,Manook M., Page E., Burghuber Ch., et al. Crosstalk Between T and B Cells in the Germinal Center After Transplantation. Transplantation 2017;101: 704–712.
Excellent response, thank you
Classical example is indirect allorecognition ; where recipient APC presents donor particles to the recipient Cd4. Cd4 get activated and stimulate B cells to differentiate in plasma cells which produces antibodies. Maintenance of high levels of immunosuppression is necessary.
Dear all, Please consider the following in responding to this scenario:
T cell population
T cell activation, and
T cells effector mechanisms
T cell paly a principal role in recognition of transplanted graft.
there are 2 main pathways:
Direct one: recipient T cells detects whole MHC of donor cells. . This is the main pathway of early rejection due to excess number of T cells.
Indirect one: in this mechanism , T cells only recognize allo molecule after processed with host APC. This is the main mechanism of chronic rejection.
T cells are the main cells of the adaptive immune response for organ transplants,they are the modurator of tolerance, rejection, and Graft versus host disease
T cell undergo allorecognition through 3 pathways
–Direct pathway :T cells reacting directly to antigens presented by donor antigen-presenting cells (APCs) ,leading to acute rejection
–Indirect pathway :T cells recognize self-APCs presenting peptides on self-HLA molecules, from donor MHC antigens leading to chronic rejection as donor APCs present in the graft are subsitituted by the recipient APC later on .
Interactions between alloreactive B cells with immunoglobulin receptors that bind donor HLA molecules and presnts it to indirectly alloreactive T cells ,recognizing the peptides from the same allogeneic HLA molecules facilitating antibody production by B cells
– Semidirect pathway : allogeneic HLA/peptide complexes from donor cells named “cross-dressing,” activate T cells
A study recognised that high numbers of recipient APCs acquire donor MHC molecules via microvesicles,triggering the semidirect pathway to cause rejection
DeWolf S and Sykes M. Alloimmune T cells in transplantation: J Clin Invest. 2017;127(7):2473–2481.
The scenario here is about T cells and their functions NOT on allorecognition pathways
T cells play a key role in transplant rejection by also recognizing foreign antigens, activating them, and orchestrating an effector response that causes organ damage.
Cellular (lymphocyte) and humoral (antibody) immunological responses to transplanted organs exist. While other cell types are involved, T cells are crucial in transplant rejection. The rejection response has two stages: sensitization and effector.
Sensitization
The CD4 and CD8 T cells detect the alloantigens expressed on the foreign graft cells through their T-cell receptors. The T cell receptor interacts with the antigen given by MHC molecules, and the costimulatory receptor/ligand interaction on the T cell/APC surface provides the second signal.
The interaction of CD28 on the T cell surface with its APC surface ligands, B7-1 or B7-2 (often known as CD80 or CD86) has been investigated the most.
Also, CTLA4 binds to these ligands and inhibits them. Other costimulatory molecules include CD40 and CD40L.
Direct pathway
In the direct pathway, host T cells recognize intact allo-MHC molecules on the surface of the donor or stimulator cell. Mechanistically, host T cells see allo-MHC molecule + allo-peptide as being equivalent in shape to self-MHC + foreign peptide and, hence, recognize the donor tissue as foreign. This pathway is presumably the dominant pathway involved in the early alloimmune response.
Indirect pathway
In the indirect pathway, T cells recognize processed alloantigen presented as peptides by self-APCs. Secondary responses such as those that occur in chronic or late acute rejection are associated with T cell proliferative responses to a more variable repertoire, including peptides that were previously immunologically silent. Such a change in the pattern of T cell responses has been termed epitope switching or spreading.
Well done Weam
Dear Dr Ibrahim
This is impressive if this was your refection just before reading. Even if with reading, you summarised very well. Excellent, keep going
The immune response to graft is by three phases : allorecognition , activation of antigen specific lymphocytes and the effector phase of graft rejection
T cells are the mediator of rejection and they are the backbone of human adaptive immune response
T cell activation : T cell recognition of antigen is the primary event that initiates the the immune response
Allorecognition :T cells recognize antigen in the form of peptide bound to major histocompatibility complex (MHC) proteins and this need two signals: signal 1 is by the interaction of the T cell receptor (TCR) with antigen presented as a peptide by the antigen-presenting cell (APC), and Signal 2 is provided by costimulatory receptor interaction on the T cell/APC cell surface .
Allorecognition can be divided into three pathways: direct, indirect, and semidirect pathways
Direct pathway:donor antigen-presenting cells (APCs) interact directly with recipient T cells .
Indirect pathway :recipient APCs present processed donor allogeneic peptides to recipient T cells.
Semidirect pathway : recipient APCs acquire donor HLA molecules that present peptides directly to recipient T cells.
once T cell activated , they undergo proliferation and differentiation , these activated T cell will induce CD8 T cell-mediated cytotoxicity, give help to B cell to produce antibodies and finally give help for macrophages to induce delayed-type hypersensitivity response
References
Susan DeWolf , Megan Sykes .Alloimmune T cells in transplantation.J Clin Invest. 2017;127(7):2473-2481.
Ali JM, Bolton EM, Bradley JA, Pettigrew GJ. Allorecognition pathways in transplant rejection and tolerance. Transplantation. 2013;96(8):681–688.
Afzali B, Lechler RI, Hernandez-Fuentes MP. Allorecognition and the alloresponse: clinical implications. Tissue Antigens. 2007;69(6):545–556.
Lakkis FG, Sayegh MH .Memory T cells: a hurdle to immunologic tolerance.J Am Soc Nephrol. 2003;14(9):2402
Pratt JR, Basheer SA, Sacks SH . Local synthesis of complement component C3 regulates acute renal transplant rejection.Nat Med. 2002;8(6):582.
Lee RS, et al. Indirect recognition of allopeptides promotes the development of cardiac allograft vasculopathy. Proc Natl Acad Sci U S A. 2001;98(6):3276–3281.
Pietra BA, Wiseman A, Bolwerk A, Rizeq M, Gill RG. CD4 T cell-mediated cardiac allograft rejection requires donor but not host MHC class II. J Clin Invest. 2000;106(8):1003–1010.
Allorecognition, that is defined as recognition of the donor alloantigen by the recipient T cell is a central event in the initiation of alloimmune response and eventually allograft rejection. The allorecognition needs to alloreactive T lymphocytes that express TCR capable of binding alloantigens.
There are vastly divers TCRs that recognize millions of alloantigens, but a given T lymphocyte, expresses a few different TCRs on its surface, allowing it to respond to a limited number of antigens.
Normally only 0.01%-0.1% of T lymphocytes of a patient recognize and response to a given microbial antigen, but in the context of transplantation, approximately 2%-10% of T lymphocyte react with mismatched allograft. Two main reasons were described for this discrepancy.
First, TCRs recognize alloantigens via three pathways: direct allorecognition, semi direct allorecognition, and indirect allorecognition. (Indirect pathway allorecognition is responsible for present microbial antigens). Allorecognition via the direct pathway are more prevalent (approximately 100 folds) compared to allorecognition via the indirect pathway (because of intrinsic bias and cross-reactivity). Direct allorecognition by T cells of intact MHC molecules has not demonstrated out of alloimmunity. So, this phenomenon uniquely distinguishes between alloimmunity from ordinary immunity to microorganisms and probably this pathway is the dominant pathway involved in early alloimmune response. Thus, direct recognition is of major importance in acute allorecognition and transplant organ that carries a high number of APCs (interstitial dendritic cells) have high intensity of allo-MHC molecules and can directly stimulate the recipient’s T cells. In the indirect pathway, T cells recognize processed antigens presented as peptides on self APC (host APC). Allopeptide-reactive T cells are present during both acute and chronic rejection. Even though primary immune responses are characterized by T cell-proliferative responses to a limited number of immunogenic MHC allopeptides, secondary responses such as those that occur in chronic or late acute rejection are associated with T cell-proliferative responses to a more variable repertoire. Such a change in the pattern of T cell responses has been termed epitope switching or spreading
Semi direct pathway: Intact donor antigen can be transferred between different T cell types, raising the possibility that direct T cell recognition of intact donor alloantigen on recipient APCs may also occur.
The second reason is the enormous presence of memory T lymphocytes in the alloreactive T lymphocyte repertoire of humans, which compared to their naïve precursors, are present at much higher frequency and have a much greater proliferative capacity once activated by antigens.
Activation of T lymphocytes requires two key signals: signal 1, interaction of TCRs with antigens presented by APC, and signal 2, costimulatory ligand/receptor interaction on T cell/APC cell surface (such as CD80/CD28)
After activation and clonal expansion under the influence of factors such as IL-2, T lymphocytes perform different functions:
Induce CD8-positive T cell-mediated cytotoxicity (cell lysis and apoptosis induction)
CD4+ T cells provide help for B-cell antibody production, and for macrophages to induce delayed-type hypersensitivity (DTH) responses.
Antigen-specific activation of T cells leads to production of cytokines and chemokines which can activate the natural immune system.
Studies have also provided a link between MHC allopeptide-primed T cells and the development of acute vascular-type rejection mediated in part by accelerated alloantibody production
Accordingly, we can say T cell activation is the cornerstone of alloreactive responses in organ transplantation.
(KEY POINTS
• Acute allograft rejection is likely mediated by indirect and direct pathway CD4 T cell alloresponses.
• Chronic allograft rejection is largely mediated by indirect pathway CD4 T cell responses. Direct pathway recognition of cross-dressed endothelial derived MHC class II alloantigen may also contribute to chronic rejection, but the extent of this contribution is unknown.
• Late indirect pathway CD4 T cell responses will be composed of heterogeneous
populations of allopeptide specific T helper cell subsets that recognize different alloantigens and are at various stages of effector and memory differentiation.
• Knowledge of the precise indirect pathway CD4 T cell responses active at late time
points in a particular individual will likely inform the development of alloantigen-specific cellular therapies and will guide immunometabolic modulation.)
Siu JHY, Surendrakumar V, Richards JA, Pettigrew GJ. T cell Allorecognition Pathways in Solid Organ Transplantation. Front Immunol 2018; 9:2548.
Well done
T cell is the main initiator of immune response, Immune response to a graft occurs in the following 5 steps :
1- Antigen source
2- Allorecognition
3- Costimulation
4- Activation of T cells, promotion of differentiation
Once costimulation occur, T cells secrete IL2 which activate T cells and promote differentiation into :
A- CD4 positive T cells if APC express HLA class II :
B- CD8-positive T cells if APC express HLA type I
5- Damage of the graft induced by :
REFERANCES
1. Matzinger P, Bevan MJ. Hypothesis: why do so many lymphocytes respond to major histocompatibility antigens? Cell Immunol 1977; 29:1.
2. Vella J, Knoflach A, Waaga A, Sayegh M. T cell mediated immune responses in chronic allograft rejection: Role of indirect allorecognition and costimulatory pathways. Graft 1998; 1:S11.
3. Durrbach A, Francois H, Jacquet A, et al. Co-signals in organ transplantation. Curr Opin Organ Transplant 2010; 15:474.
Excellent summary
An updated References list would add a lot
T cells activation is the main step in activation of immune response. Once the T cells recognize the donor Ag, it will differentiate into cytotoxic (directly kill the foreign Ag) & helper ( help other immune cells through membrane receptors & cytokine production) lymphocytes.
Also helper T cells can induce B lymphocytes to produce antibodies against graft.
Normally T cells compromised 0.01-0.1% of total lymphocytes but after transplantation it increased to 2-10% of total lymphocytes. This increase in number of T cells after transplantation is explained by :
T cells need 3 steps or signals to complete their full maturation & differentiation :
Signal I: the activation of T cells will be through CD3 complex in association with TCR
Signal II: in this step the T cell complete their differentiation into effector lymphocytes. It occur through co stimulatory receptors on T cells that ligand on APC.
Signal III: involve the production of cytokines BY APC or T lymphocytes.
References:
Handbook of Transplantation. Gabriel M. Danovitch. 6th ed.
Thanks Ban
Use your own words please. I admire your contribution. Well done