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.
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?
1-Calcinurin inhibitors decrease T-reg viability and proliferation.
2-The effects of mycophenolic acid on T-reg appear to be more variable .
3-Glucocorticoids appear not to affect T-regs.
4-mTOR inhibitors promote differentiation and expansion of T-reg as well as increase Foxp3expression,although their effect may decline over time .
5-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.
6-There are none immunosuppressive drugs have been shown to increase T-reg population; Metformin and Erythropoietin
References ;
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 mammalian target of rapamycin 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
Ahmed Fouad Omar
3 years ago
What is Treg and how it is activated?
T regulatory (Treg) cells are a subclass of CD4 T cells that is responsible for suppression of immune response . it is either thymus derived( tTregs) or peripheral derived (pTregs)
Characterized by expression of CD4, CD25 and FOXP3 (CD4+CD25+FoxP3+)
It was found that mutation in FOXP3 locus is associated with Treg dysfunction that lead to severe autoimmunity
Transformation of naïve CD4+ T cell to pTreg occur due to repeated stimulation to non- self antigen or exposure to certain cytokines (IL10, TGF-β)
What is the proposed mechanism(s) of induction of tolerance by Treg?
Treg is important in initiating and maintaining peripheral tolerance as they suppress immune response by either contact inhibition through surface expression of CTLA-4 medicated by Foxp 3 or by non contact inhibition through the release of IL10, TGF-β
The net result is suppression CD4 T cell, suppression of CD8+ T cells, and may suppress B cells and dendritic cells.
How would you implement Treg monitoring in clinical transplantation
Tregs can be monitored in clinical transplantation by the specific markers related to Treg including FOXP3, CD25, CTLA4, GITR and CD127. (3) These markers are T cell activation markers, hence they are not specific for Treg.
Tregs have been used in clinical trials in transplantation as a way to induce tolerance. Deuterium labelled pTregs have been used in kidney transplant recipients. (4) Post transfusion, these could be tracked by their deuterium signals. Similarly, Indium labelled T regs have also been transfused in kidney transplant recipients and monitored using SPECT. REFERANCES 1) Corthay A. How do regulatory T cell work? Scand J Immunol 2009;70:326-336. 2) Chandran S, Tang Q, Sarwal M, et al. Polyclonal regulatory T cell therapy for control of inflammation in kidney transplants. Am J Transplant 2017;17:2945-2954. 3) Hutchinson JA, Riquelme P, Sawitzki B, et al. Cutting Edge: Immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients. J Immunol 2011;187:2072-207
4) Herzog RW, Kuteyeva V, Saboungi R, Terhorst C, Biswas M. Reprogrammed CD4(+) T cells that express FoxP3(+) control inhibitory antibody formation in hemophilia A mice. Front Immunol. (2019) 10:274
5). Jaeckel E, von Boehmer H, Manns MP. Antigen-specific FoxP3-transduced T-cells can control established type 1 diabetes. Diabetes. (2005) 54:306–10.
6). Beavis PA, Gregory B, Green P, Cribbs AP, Kennedy A, Amjadi P, et al. Resistance to regulatory T cell-mediated suppression in rheumatoid arthritis can be bypassed by ectopic foxp3 expression in pathogenic synovial T cells. Proc Natl Acad Sci USA. (2011) 108:16717–22.
Ahmed Omran
3 years ago
T reg have important role in immune homeostasis and balance of immune response. They are of 2 main types:
. Thymus -derived CD4+CD25+Foxp3,nTreg
.Adaptive /induced T reg from peripheral naiive cells
Foxp3 is the major transcription factor which influences behavior and function of T reg cells. T reg produce cytokines like TGFB,IL-10,and IL-35.Th3 cells produce TGBF and Tr1 secrete IL-10.
MMF and rapamycin expand iT reg. CNI inhibit T reg function through targeting IL-2 production. Tac inhibits IL-2 production .Post Tx effect of immunosuppressive agents on T reg must be put in consideration .
References:
Bryan ,E et alT reg induction ,migration ,and function in transplantation,J immunol,2012,Nov 15;189(10):4705-4711
Mohamed Essmat
3 years ago
Regulatory T cell is a type of CD4+ T cells that elicit regulatory or immunosuppressive actions. They provide immune tolerance against self-antigens.
Treg activation is antigen dependent process.
Various mechanisms of action of Treg including:
*Contact dependent suppression
*Contact-independent suppression through anti-inflammatory cytokine production.
*Inducing apoptosis through Granzyme/perforin pathways.
Tregs can be monitored by the specific markers related to Treg including FOXP3, CD25, CTLA4, GITR and CD127. These markers are T cell activation markers.
Tregs have been used in trials in Tx aiming for tolerance induction.
Last edited 3 years ago by Mohamed Essmat
AMAL Anan
3 years ago
Regulatory T cells in the peripheral circulation are characterised as CD4+ with high levels of IL‐2 receptor alpha chain (CD25high) and low levels of CD127 and intracellularly, expressing the forkhead box P3 transcription factor (FOXP3+).However, the adoption of novel deeper immunophenotyping technologies has identified this phenotype to be more heterogeneous than initially considered.These data differ depending on the species, type of Treg cells, differentiation state and microenvironment.Hence, a comprehensive understanding of Treg cell heterogeneity is needed to safely and effectively exploit their therapeutic potential. As such, we consider it timely in this review to outline established and novel data regarding Treg heterogeneity and discuss future lines of inquiry.
In solid organ and bone marrow transplantation (SOT and BMT, respectively), Treg cells have been identified as modulators of both T‐cell‐mediated and antibody‐mediated rejection.However, our understanding of the underlying mechanisms is complicated as effector T cells (Teffs) can adopt the Treg‐like phenotype and functions. In reverse, Treg cells can alter their phenotype and functions to adopt a Th17‐like effector cell profile too. It is important to understand these alterations as they can impact the regulatory balance in the graft.A further limitation is that much of our understanding to date originates from in vitro experiments and in vivo murine (or non‐human primate; NHP or swine) models.It is only in recent years through clinical trials can the in vivo relevance of these mechanisms to humans undergoing SOT be deciphered. These trials mainly involve ex vivo expansion of autologous Treg cells under Good Manufacturing Practice (GMP) conditions utilising various pharmacological agents that promote their differentiation, expansion, stability and function.Considering this recent progress, we consider it timely to outline the recent clinical trials in SOT with a focus on safety.
References
1. Christians U, Klawitter J, Klawitter J et al Biomarkers of immunosuppressant organ toxicity after transplantation: status, concepts and misconceptions. Expert Opin Drug Metab Toxicol. 2011; 7: 175–200.
2. Bahmani B, Uehara M, Jiang L et al Targeted delivery of immune therapeutics to lymph nodes prolongs cardiac allograft survival. J Clin Invest 2018; 128: 4770–4786.
3. Graca L, Cobbold SP, Waldmann H. Identification of regulatory T cells in tolerated allografts. J Exp Med 2002; 195: 1641–1646. [PMC free article] [PubMed] [Google Scholar]
4. Lee I, Wang L, Wells AD et al Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor. J Exp Med 2005; 201: 1037–1044.
AMAL Anan
3 years ago
What is the proposed mechanism(s) of induction of tolerance by Treg?
Defining the mechanisms of Treg-cell function is clearly of crucial importance. Not only would this provide insight into the control processes of peripheral tolerance but it would probably provide a number of potentially important therapeutic targets. Although this quest has been ongoing since interest in Treg cells was reignited in 1995, there has been significant progress in the last few years. From a functional perspective, the various potential suppression mechanisms of Treg cells can be grouped into four basic ‘modes of action’: suppression by inhibitory cytokines, suppression by cytolysis, suppression by metabolic disruption, and suppression by modulation of dendritic-cell (DC) maturation or function.
Inhibitory cytokines, such as interleukin-10 (IL-10) and TGFβ, have been the focus of considerable attention as a mechanism of Treg-cell-mediated suppression. There has also been significant interest in their ability to generate induced (also known as adaptive) Treg-cell populations, either naturally in vivo or experimentally as a potential therapeutic modality. Although the general importance of IL-10 and TGFβ as suppressive mediators is undisputed, their contribution to the function of thymus-derived, natural Treg cells is still a matter of debate.This is partly due to the general perception that Treg cells function in a contact-dependent manner. Indeed, in vitro studies using neutralizing antibodies or T cells that are unable to produce or respond to IL-10 and TGFβ suggested that these cytokines may not be essential for Treg-cell function. However, this contrasts with data from in vivo studies.
* Suppression by inhibitory cytokines:
~ Inhibitory cytokines, such as interleukin-10 (IL-10) and TGFβ, have been the focus of considerable attention as a mechanism of Treg-cell-mediated suppression. There has also been significant interest in their ability to generate induced (also known as adaptive) Treg-cell populations, either naturally in vivo or experimentally as a potential therapeutic modality.
* Suppression by cytolysis:
~ Cytolysis mediated through secretion of granzymes had long been considered the forte of natural killer (NK) cells and cytotoxic CD8+ T lymphocytes (CTLs).
*Suppression by metabolic disruption:
~Several intriguing suppressive mechanisms have been described that could collectively be referred to as mechanisms that mediate ‘metabolic disruption’ of the effector T-cell target. A long-standing debate in the Treg-cell field is whether the high expression of CD25 empowers Treg cells to ‘consume’ local IL-2 and therefore starve actively dividing effector T cells by depleting the
IL-2 they need to survive.
*Suppression by targeting dendritic cells:
~In addition to directly affecting effector T-cell function, Treg cells might modulate the maturation and/or function of dendritic cells (DCs) required for effector T-cell activation. This has long been considered an attractive idea but there has been only limited data in support80. However, intravital microscopy has revealed direct interactions between Treg cells and DCs in vivo, which was proposed to attenuate effector T-cell
activation by DCs.
References:
1. Sakaguchi S, et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol. Rev. 2001;182:18–32.
2. Shevach EM, et al. The lifestyle of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells. Immunol. Rev. 2006;212:60–73.
3. Xystrakis E, Boswell SE, Hawrylowicz CM. T regulatory cells and the control of allergic disease. Expert. Opin. Biol. Ther. 2006;6:121–133.
4. Coombes JL, Robinson NJ, Maloy KJ, Uhlig HH, Powrie F. Regulatory T cells and intestinal homeostasis. Immunol. Rev. 2005;204:184–194.
5. Belkaid Y. Regulatory T cells and infection: a dangerous necessity. Nat Rev. Immunol. 2007;7:875–888.
AMAL Anan
3 years ago
What is Treg and how it is activated?
T regulatory (Treg) cells are a T lymphocyte subpopulation that control the balance between immune activation and tolerance. Treg cells can originate from two main sources: thymus-generated natural Tregs (tTreg) and peripheral inducible Tregs (pTreg), generated during immune priming. Several factors are required for tTreg generation; these cells are strongly dependent on TCR and CD28 signals and on several cytokines. Cytokines contribute to Treg maintaining via 𝛾 chain signaling of IL-2 and IL-15, and TGF𝛽 increases FOXP3 expression.However, certain cytokines like as TNF-𝛼 have a controversial role in tTreg generation.
On the other hand, pTreg generation requires stimulation in an anti-inflammatory milieu, a process where dendritic cells are critically involved. According to cytokine production, Tregs have been further classified; for instance, Th3 cells are characterized by TGF𝛽 production; Tr1 cells produce IL-10, and Tr35 cells produce IL-35. The suppressive capacity of these sub- sets is contact-independent. While the expression of the transcription factor FOXP3 can be transient in humans, this factor is associated with a suppressive function in mice. Thus, mouse Treg cells show the classical phenotype CD3+CD4+CD25+FOXP3+ .
***Molecular Mechanisms of Treg-Mediated Suppression:
~Several action mechanisms by which Treg cells control the immune response have been reported:
(1) inhibition by immunoregulatory cytokines such as TGF𝛽, IL-10, and IL- 35.
(2) inhibition by cytolysis of effector cell by producing granzyme and perforin.
(3) metabolic interruption, including an inhibition of the proliferative response via IL-2 receptor, cAMP-mediated metabolic inhibition, and immunomodu- lation mediated by the A2 adenosine receptor.
(4) inter- action with dendritic cells that modulates their function and maturation.
***References:
1-A. Schmidt, N. Oberle, and P. H. Krammer, “Molecular mechanisms of treg-mediated T cell suppression,” Frontiers in Immunology, vol. 3, article 51, 2012.
[2]A.L.Perdigoto,L.Chatenoud,J.A.Bluestone,andK.C.Herold, “Inducing and administering tregs to treat human disease,” Frontiers in Immunology, vol. 6, article 654, 2016.
[3] D. A. A. Vignali, L. W. Collison, and C. J. Workman, “How regulatory T cells work,” Nature Reviews Immunology, vol. 8, no. 7, pp. 523–532, 2008.
[4] M. Dhainaut and M. Moser, “Mechanisms of surveillance of dendritic cells by regulatory T lymphocytes,” Progress in Molecular Biology and Translational Science, vol. 136, pp. 131– 154, 2015.
[5] M. Saraiva and A. O’Garra, “The regulation of IL-10 production by immune cells,” Nature Reviews Immunology, vol. 10, no. 3, pp. 170–181, 2010.
Ahmed mehlis
3 years ago
●Definition of t. Reg how it is activated ?
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.[2] 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.
The following represent some of the proposed mechanisms of immune suppression:
. Regulatory T cells produce a number of inhibitory cytokines. These include TGF-β,Interleukin 35,and Interleukin 10. It also appears that regulatory T cells can induce other cell types to express interleukin-10.Regulatory T cells can produce Granzyme B, which in turn can induce apoptosis of effector cells. Regulatory T cells from Granzyme B deficient mice are reported to be less effective suppressors of the activation of effector T cells.Reverse signalling through direct interaction with dendritic cells and the induction of immunosuppressive indoleamine 2,3-dioxygenase.Signalling through the ectoenzymes CD39 and CD73 with the production of immunosuppressive adenosine.Through direct interactions with dendritic cells.
●mechanism of tolerance induction by t reg cells?
potential suppression mechanisms of Treg cells can be grouped into four basic ‘modes of action’: suppression by inhibitory cytokines, suppression by cytolysis, suppression by metabolic disruption, and suppression by modulation of dendritic-cell (DC) maturation or function .
Tregs constitute 5% to 10% of peripheral CD4 T cells in Normal healthy humans and
have a major role in immune homeostasis and in suppressing unwanted inflammatory.
Responses to self-antigens.Foxp3 was identified as the key transcription factor that
characterizes this lineage of Thymically derived Tregs.(1)
In addition to CD4þFoxp3þ Tregs, there other T-cell Subsets with suppressive activity.
These include CD4þ type 1Treg that secrete interleukin (IL)-10, 21 transforming growth
Factor-b (TGF-b) Tregs (TH3 cells), regulatory natural killer T Cells, regulatory T cells,22
and double-negative Tregs andCD8þ Tregs.17.
Functional characteristics:
The suppressive function:
of Tregs includes direct cell contactand regulatory cytokines such as TGF-b and IL-10.
Tissue-repair capacity of Tregs:
Tregs, in addition to reduce inflammation and supporting tissue repair.
Alternative Tregs subsets:
Tregs have been shown to effectively reduce renal injury in animal models of kidney
disease and injury.
The role of Tregs in tolerant kidney transplant:
Foxp3 Tregs have been shown to play important Role in the induction and maintenance
of renal allograft tolerance in various animal transplant models.
One of most valuable models is donor-specific tolerance of renal allografts.
Blocking costimulatory pathways:
Can induce allograft tolerance in major histocompatibility complex (MHC) mismatched
kidney transplant.(2)
Recent data suggest that Foxp3þ Tregs both limit graft-versus-host diseaseand maintain
mixed chimerism, assisting in tolerance development in mixed- and full-chimerism
models of kidney allograft tolerance and that their numbers are potentially
increased in the transplanted organ.
High levels of FOXP3⁺ Tregs, specifically CXCR3⁺ Tregs and HLA-DR high⁺ CD45RA_
Tregs in peripheral blood that produce high levels of interferon-g, are associated with
renal allograft survival and function.TGF-b and IL-10 have both been identified as being
associated with long-term renal allograft acceptance.Induced Tregs secreting interferon-g demonstrate suppressive function in vitro and are associated with renal
allograft acceptance in kidney transplant patients.
Treg therapy in kidney disease and transplantation.
Anti-CD3 and CD28 antibodies, with IL-2and/or rapamycin, these have been shown to be
potent and therapeutic in limiting rejection.
Reference:
1- Min Hu. Yuan Min Wang.Yiping Wang et al. Regulatory T cells in kidney disease
and transplantation. Kidney International (2016) 90, 502–514.
2-1- Min Hu. Yuan Min Wang.Yiping Wang et al. Regulatory T cells in kidney disease
and transplantation. Kidney International (2016) 90, 502–514.
Ibrahim Omar
3 years ago
1- What is Treg and how it is activated?
Tregs are a sub-population of lymphocytes and represent 5 % of the total lymphocytic count in the blood. they are of CD4+ type and express 2 major cell surface markers which are CD25 and CTLA-4 (T lymphocyte antigen 4).
Tregs are usually present in the inactive form. however, during inflammatory states, some mediators are released and activate Tregs. of these mediators areTGF-B and IL-12. furthermore, during specific immune reactions on encountering a foreign antigen presented on an antigen presenting cells to CD4+ cells, these CD4+ cells will be activated and undergo differentiation into certain sub-types including Tregs.
2- What is the proposed mechanism(s) of induction of tolerance by Treg?
activated Tregs release some inhibitory cytokines, mainly IL-10 and IL-35. these cytokines do suppression of activated antigen presenting cells, NK cells and T lymphocytes. this will result in less immune reactions and tolerance to transplanted organs.
CTLA-4 is also responsible for adequate inhibition of T-cell activation by down-regulation of expression of co-stimulatory molecules CD80 and CD86 on dentritic cells. finally, T cell reactions will be suppressed and so induction of tolerance.
3- How would you implement Treg monitoring in clinical transplantation?
Tregs have gained a high attraction in managing an early or even a predictive marker of rejection and graft loss. Foxp3 was highly considered and already tested in urine samples and also histopathological samples in many reasonable studies. other related markers were also studies however benefits are still lacking and waiting larger and high-powered studies.
Theepa Mariamutu
3 years ago
Regulatory T cell
• T cell which regulate and suppress immune system
• Produced by normal thymus called natural
• Formed by differentiate of naïve T cell outside the thymus ( the peripheral or in cell culture called adaptive)
• Treg are CD4+ Cd 25+ due to expressing both CD 4 T cell co receptor and CD 25
• Forkhead box P3 ( FoxP3) which determines natural Treg development and fucntion
Role of T reg
• Suppress activation, proliferation and cytokine production of CD4+ T cell and CD 8+ T cell
• Thought to suppress B cell and dendritic cells
• Produce soluble messengers which have a suppressive function such as TGF-beta, IL-10 and adenosine
• Markers of natural Treg – CD152(CTLA-4) and GITR( glucocorticoid induced TNF receptor)
Different types of T cells with regulatory activity:
1. CD4+ Tcells
2. CD8+ T cells
3. Double negative T cells
4. Natural killer (NK) T cell
Treg cell heterogeneity
• Natural T cell (nTreg) / tTreg – grow in the thymus
• pTreg – develop at the perphery by specific stimuli of conventional CD4+ T cell
• iTreg-T cell induced in vitro
Proposed mechanism(s) of induction of tolerance to donor antigens
1. Deletion to donor reactive cells centrally in the thymus and in the peripheral
2. T cell ignorance, or a state of T cell unresponsiveness that is relevant to graft placed at “ immunologically privileged” sites such as the cornea or brain
3. Exhaustion – which the ability of donor -reactive cells to harm the allograft is eliminated as a result of over stimulation and cell death
4. Anergy – state of unresponsiveness that is refractory to further stimulation despite the continuing presence of antigen after transplantation
5. Immunoregulation – an active process whereby the immune response to an allograft is controlled by populations of regulatory immune cells
Treg suppressive mechanisms
• Tregs are able to suppress different cell types by direct and indirect mechanisms
• Direct mechanisms – secretion of cytokines such as IL-10, TGFβ and IL-35 and the production of granzyme and perforin, enzymes leading to apoptosis in target cells
• Indirect mechanisms –expression of CD39/CD73, which deplete the microenvironment of extracellular ATP via the generation of adenosine and AMP, molecules with immunosuppressive effects
• They can sequester, by the high expression of CD25, IL-2 from the microenvironment reducing effector T cells proliferation
• IL-2 starvation reduces NKs from proliferating and exhibiting effector functions
• NKs can be directly affected by Tregs in a membrane bound TGF-ß dependent manner
• Tregs have been observed to have a direct effect on B-cells via PDL1/PD-1 interaction and DCs via both CTLA-4 and LAG-3. CTLA-4 blocks co-stimulation reducing CD80/CD86 expression and it induces upregulation of Indoleamine 2,3-dioxygenase
• The expression of CD39 on Tregs mediate the conversion to ATP to adenosine and AMP and reduce T effector proliferation
• Tregs can also skew monocyte toward M2 macrophages and prevent their differentiation in pro-inflammatory M1 macrophages. They can similarly induce a suppressive phenotype in neutrophils and reduce ILC2 cytokine secretion
The TRACT trial -Immunophenotypic analysis of the subjects shows a significant (9- to 20-fold) increase in the percentage of circulating CD4+CD127–CD25hiFoxp3+ cells in peripheral blood. The authors concluded that the safety of the phase I trial allows planning for a phase II trial; however, because the Tregs were infused following severe T cell depletion, the percentage increase in Tregs may not be meaningful or clinically relevant if the absolute number of Tregs is very low.
TASKp trial- showed that Treg infusions were safe and were not associated with acute side effects, nor did infusion precipitate episodes of acute rejection. Kidney biopsies performed 2 weeks after the infusion showed a marked decrease in inflammation in two of three patients that was associated with a concomitant decrease in inflammatory gene expression. The deuterium label used to track the infused Tregs was found exclusively in the Treg population. The results of this pilot study suggest that maintenance immunosuppression did not negatively impact Treg pharmacokinetics or lineage stability.
The TASK trial-Renal allograft inflammation below the threshold of rejection is a unique setting for testing the therapeutic effect of Tregs. Routine protocol kidney biopsies in patients with stable renal function show that 10%–20% have inflammatory mononuclear cell infiltration in the renal graft. There is no consensus about what remedial therapy, if any, to use for subclinical inflammation
implement Treg monitoring in clinical transplantation
Few questions to be answered before implementations
1. What is the optimum dosage of Tregs?
2. Are alloantigen-reactive Tregs required for efficacy as compared with polyclonal Tregs, how about the price of manufacturing vs benefit?
3. A single Treg infusion enough to induce tolerance, thereby extending the biological effects of Tregs indefinitely, or require frequent dosing to replenish Tregs?
4. What are the specific requirements, particularly for adjunct immunosuppressants, to maximize the survival and function of infused Tregs?
I would like to use Tregs have been proven in clinical trials in transplantation to induce tolerance. Deuterium labelled pTregs have been used in kidney transplant recipients. Post transfusion, these could be monitored by their deuterium signals. Indium labelled T regs have also been transfused in kidney transplant recipients and monitored using SPECT. Probably for now, these metjodas can be used while searching for more evidences role of Treg in monitoring post tranplantation.
References
Muhammad Atif, Filomena Conti.Regulatory T cells in solid organ transplantation.
Clin Transl Immunology. 2020; 9(2): e01099.
Hu, M., Rogers, N. M., Li, J., Zhang, G. Y., Wang, Y. M., Shaw, K., O’Connell, P. J., & Alexander, S. I. (2021). Antigen Specific Regulatory T Cells in Kidney Transplantation and Other Tolerance Settings. In Frontiers in Immunology (Vol. 12).
Malhotra, Deepali; Linehan, Jonathan L. Tolerance is established in polyclonal CD4+ T cells by distinct mechanisms according to self-peptide expression patterns. Nature Immunology.2016: 17 (2): 187–195.
Kidney transplantation: Principles and Practice by Stuart J Knechtile
Handbook of kidney transplantation by Gabriel M. Danovitch
Nasrin Esfandiar
3 years ago
T regs are a subgroup of T cells that have immunoregulatory effects. 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.
· Tregs or regulatory Tcells are important to induce tolerance by expression of CD25 or secretion of IL-10 and TGF β.
· IFN- γ can induce T regs and inhibit Th 17 cells.
1. Issa F, Schiopu A, Wood KJ. Role of T cells in graft rejection and transplantation tolerance. Expert Rev Clin Immunol. 2010 Jan;6(1):155-69.
2. Hu, M., Rogers, N. M., Li, J., Zhang, G. Y., Wang, Y. M., Shaw, K., O’Connell, P. J., & Alexander, S. I. (2021). Antigen Specific Regulatory T Cells in Kidney Transplantation and Other Tolerance Settings. In Frontiers in Immunology (Vol. 12). https://doi.org/10.3389/fimmu.2021.717594
Dalia Ali
3 years ago
Treg
are important in maintaining immune homeostasis and in regulating a variety of immune responses, making them attractive targets for modulating immune-related diseases.
There are two main types of Treg: thymus-derived CD4+CD25+Foxp3+ natural Treg (nTreg), and adaptive/induced Treg (iTreg) that develop from naïve T cells in the periphery under tolerogenic conditions .
It has long been established that Fork-head box P3 (Foxp3) is the major transcription factor (TF) that determines the fate, identity, and function of Treg, and Treg regulate immune functions by producing cytokines such as TGFβ, IL-10, and IL-35 (3, 4). However, there are subsets of Treg that do not express Foxp3. For example, TGFβ-producing Th3 and IL-10-secreting Tr1 regulatory T cells also can be potent suppressors in some experimental systems.
Common immunosuppressants used post-transplantation in humans have opposing effects on Treg induction. Both mycophenolate mofetil, an inosine 5’-monophosphate dehydrogenase inhibitor, and rapamycin, the eponymous inhibitor of the mammalian target of rapamycin (mTOR), expand iTreg in vitro and in vivo .In humans, rapamycin (sirolimus) given following treatment with a lympho-depleting anti-CD52 mAb favors Treg expansion
calcineurin inhibitors may prevent Treg induction .Cyclosporine A inhibits Treg function and proliferation .likely by inhibiting IL-2 production .This inhibition of Treg function and proliferation allows for effector T cell proliferation and prevention of peripheral repopulation of Treg following anti-CD52 mAb treatment
FK506 (tacrolimus) also inhibits the transmission of TCR signaling, thus inhibiting IL-2 production. Reports regarding the impact of FK506 on Treg induction vary; it has been reported to inhibit, not affect, or favor Treg induction, likely in a dose-dependent fashion .Thus, post-transplantation immunosuppressive regimens should be chosen with care in order to promote the generation and function of protective Treg and suppress anti-graft immune responses.
Bryna E. Nakayama Y,Treg induction, migration, and function in transplantation. J Immunol. 2012 November 15; 189(10): 4705–4711. doi:10.4049/jimmunol.1202027.
Exellant Dalia well understood controvertial relation of IS and Tregs.
Ben Lomatayo
3 years ago
Regulatory T cells consist of natural Treg and adaptive T reg cells. They control the type and magnitude of immune response to a foreign antigen, ensuring that the host remain undamaged. They include ; 1. Thymus-derived regulatory T cells 2. Peripherally-derived regulatory T cells 3. inVitro-induced regulatory T cells. Treg expresses FOXP3 proteins.
Mechanism of Tolerance ;
1.Central Tolerance ; a) Anergy b) Deletion c) Receptor editing ( gene rearrangment )
2. Peripheral Tolerance; a) Deletion and apoptosis b) anergy c) Regulation or Suppression
Monitoring of T reg can done through FOXP3
References ;
Eergton M, Scollay R, Shortman (1990) kinetics of mature T- cell development in the thymus. Proc Natl Acad Sci 87: 2579-82
Russel DM, Dembic Z, Morahan G (1991) peripheral deletion of self-reactive B cells. Nature 354: 308-311
Jiang H, Wu Y, Liang B, Zheng Z, Tang G, et al.(2017) An affinity avidity model of peripheral T cell regulation. Journal of clinical investigation 115: 302 -312.
Thnx Prof ;
Thymus derived Treg is the main mediator of central immune tolerance, while peripherally derived T reg regulate peripheral immune tolerance
Anergy ; is hypo-responsiveness of T or B cells to further antigenic stimulation
Reciptor editing ; A new BCR with altered specificity is generated
Deleption & apoptosis ; is Activation – Induced Cell Death through Fas- Fas-L interactions
Nadia Ibrahim
3 years ago
What is Treg? Tregs are CD4+CD25high T lymphocytes expressing FoxP3 transcription factor According to origin Tregs originate in 2 sites,(1) the thymus (tTreg) during the course of positive and negative selection ,(2) peripherally [pTreg) which originate from nonregulatory Foxp3− CD4 T cells (Tconv) after exposure to antigenic stimulation and transforming growth factor-β signaling) three Treg subsets have been described. central Treg (cTreg), effector Treg (eTreg), and memory Treg (mTreg) Tregs play a central role in maintaining immune homeostasis, promoting and maintenance of allograft tolerance (1) Prevention of chronic rejection and participate in tissue repair. differentiation from cTregs to eTregs is critical for the maintenance of immune homeostasis and self-tolerance (2). mTregs are considered to be a subset of Tregs in nonlymphoid tissues, of a low proliferative state in absence of their cognate antigen Upon re-exposure to cognate antigen, mTregs expand and provide protection against excessive damage (3).
how it is activated? Treg subsets are activated Upon T cell receptor (TCR) ligation and co-stimulation during antigen presentation by self-MHC class II on recipient APCs. cTregs that are accumulated in lymphoid organs differentiate into eTregs (4) That then infiltrate both lymphoid and nonlymphoid organs What is the proposed mechanism(s) of induction of tolerance by Treg? (1) expression of transcription factors typical of effector cells toward Th1, Th2, or Th17. · expression of T-bet+TIGIT towards Th-1 · transcription factor IRF-4 towards Th-2 · expression of the Th17-typical factor STAT3 to the regulation of the Th17-mediated immune response and enables the expression of IL-10, Ebi3, granzyme-B, and perforin-1 genes (5) (2) Antigen-specific suppression caused by the direct Treg–DC (dendritic cell) interaction enabled by the recognition of the specific antigen (Ag) the DC presents as part of MHC-II ,evntually ends in disruption of Ag presentation, cause T effector anergy, or trigger Ag-specific pTreg induction. (3) Antigen-non-specific mechanisms include: · enzymes CD39/CD73 on the Treg surface, which cause ATP to degrade to adenosine. Increased adenosine concentration in the microenvironment inhibits DC presentation of antigens and suppresses the proliferation of activated T effectors (6). · non-specific suppression factors: Treg production of cytokines: TGF-β, IL-10, and IL-35. They can suppress the activation and proliferation of effector T and B lymphocytes; inhibit antigenic presentation to dendritic cells, which in their turn enable pTreg induction (4) Ccontact suppression mechanism: · Treg disrupt the Ca2+ supply to effector lymphocytes, thus disabling the Ca2+-dependent transcription factors NFAT and NF-kB T effectors need in early TCR-dependent activation. · Perforin-granzyme cytolysis against a CD4+, and CD8+ effector T cells. (5) Tumor necrosis factors . As Tregs are activated, they acquire TRAIL (TNF-related apoptosis-inducing ligand) expression, while the CD4+ effector cells begin expressing the ligand of this molecule, DR5 (death receptor 5); TRAIL/DR5 interaction induces the apoptosis in effector lymphocytes (6) Treg lymphocytes simultaneously express the molecule PD-1 and its ligand PD-L1. DC PD-L1 and Treg PD-1 interaction generates a tolerogenic dendritic cell. Treg PD-L1 interacts with PD-1 on the activated effector cells and causes its anergy). (7) Because of high IL-2R (CD25) expression, Tregs can reduce IL-2 concentrations in the microenvironment, which will negatively affect the proliferative response of CD8+ cells. How would you implement Treg monitoring in clinical transplantation? Through Molecular markers, although they are not truly Treg-specific as also can be found in activated conventional Th cells. · CD25 · cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) · glucocorticoid-induced tumour necrosis factor receptor family-related gene (GITR) · lymphocyte activation gene-3 (LAG-3) · CD127 · forkhead/winged-helix transcription factor box P3 (Foxp3) Effect of immunesuppression on T reg population: Negatively affecting Tregs · Calcineurin inhibitors
o ◦Cyclosporine A
o ◦Tacrolimus (FK506) Inhibit calcineurin and NFAT activation, which destabilizes Foxp3 expression in Tregs · Belatacept (CTLA-Ig) Blocks signaling through co-stimulatory molecule CD28, which is essential for Treg ontogeny and function · Basiliximab (anti-IL-2R) Blocks IL-2 receptor signaling Positively affecting Tregs · mTOR inhibitors
o ◦Rapamycin
o ◦Everolimus Inhibit mTORc1 activity. Tregs appear to be less sensitive to mTORc1 inhibition than Tconv · HDAC inhibitor
o ◦Vorinostat Inhibits histone deacetylases and promotes gene expression · Low-dose IL-2 Promotes IL-2R signaling on Tregs. Tregs are more sensitive to low-dose IL-2R signaling than Tconv · Rabbit anti-thymocyte globulin (rATG) Depletes both Tconv and Tregs, but Tregs numbers recover faster than Tconv No or unknown effects on Tregs · Complement inhibitors
o ◦Eculizumab Prevent C5 cleavage. No effect on Treg numbers, but function was not assessed83 · Steroids
o ◦Prednisone
o ◦Methylprednisolone Inhibit pro-inflammatory cytokines. No effects on Tregs in transplant patients92 · Antiproliferative agents
o ◦Mycophenolate mofetil (MMF)
o ◦Azathioprine Inhibit purine synthesis. Unknown effects on Tregs Ref: (1) Tang Q, Bluestone JA. The Foxp3 + regulatory T cell: a jack of all trades, master of regulation. Nat Immun. 2008;9:239–44. [PMC free article] [PubMed] [Google Scholar] (2) Nagy ZA. Evolutionary origin of the immune system: a dialogue with Rod Langman. Scand J Immunol. 2008;67:313–21. [PubMed] [Google Scholar]
(3) Wang R, Song L, Han G, et al. Mechanisms of regulatory T-cell induction by antigen-IgG-transduced splenocytes. Scand J Immunol. 2007;66:515–22. [PubMed] [Google Scholar]
(4) Cohn M. A rationalized set of default postulates that permit a coherent description of the immune system amenable to computer modeling. Scand J Immunol. 2008;68:371–80. [PMC free article] [PubMed] [Google Scholar] (5) Chaudhry A, Rudra D, Treuting P, Samstein RM, Liang Y, Kas A, et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science. (2009) 326:986–91. doi: 10.1126/science.1172702 PubMed Abstract | CrossRef Full Text | Google Scholar (6) Ernst PB, Garrison JC, Thompson LF. Much ado about adenosine: adenosine synthesis and function in regulatory T cell biology. J Immunol. (2010) 185:1993–8. doi: 10.4049/jimmunol.1000108 PubMed Abstract | CrossRef Full Text | Google Scholar
Thankyou Nadia your comments about IS and Tregs is very clear.
Asmaa Khudhur
3 years ago
Regulatory T cells (Tregs) are a specialized subpopulation of T cells that act to suppress immune response, maintain tolerance to self antigens and prevent autoimmune diseases thereby maintaining homeostasis . It has been shown that Tregs are able to inhibit T cell proliferation and cytokine production and play a critical role in preventing autoimmunity.
Treg cells express the biomarkers CD4 ,FOXP3 and CD25and are thought to be derived from the same lineage as naïve CD4+cells.
Different subsets with various functions of Treg cells exist. Tregs can be usually identified by flow cytometry. The most specific marker for these cells is FoxP3, which is localized intracellulary. Selected surface markers such as CD25high (high molecular density) and CD127low (low molecular density) could serve as surrogate markers to detect Tregs in a routine clinical practice. Dysregulation in Treg cell frequency or functions may lead to the development of autoimmune disease. Therapeutical Treg modulation is considered to be a promising therapeutical approach to treat some selected disorders, such as allergies, and to prevent allograft rejection.
Treg cells can originate from two main sources: thymus-generated natural Tregs (tTreg) and peripheral inducible Tregs (pTreg), generated during immune priming.
Several factors are required for tTreg generation; these cells are strongly dependent on TCR and CD28 signals and on several cytokines. Cytokines contribute to Treg maintaining via γ chain signaling of IL-2 and IL-15, and TGFβ increases FOXP3 expression .However, certain cytokines like as TNF-α have a controversial role in tTreg generation .
On the other hand, pTreg generation requires stimulation in an anti-inflammatory milieu, a process where dendritic cells are critically involved .
According to cytokine production, Tregs have been further classified; for instance, Th3 cells are characterized by TGFβ production; Tr1 cells produce IL-10, and Tr35 cells produce IL-35. The suppressive capacity of these subsets is contact-independent. While the expression of the transcription factor FOXP3 can be transient in humans, this factor is associated with a suppressive function in mice.
Reference:
Regulatory T cells (TREG) and their roles in immune system with respect to immunopathological disorders
Katerina Kondĕlková et al. Acta Medica (Hradec Kralove). 2010.
Regulatory T Cells: Molecular Actions on Effector Cells in Immune Regulation
What is Treg and how it is activated?
It’s subclass of both Cd4Tcell and cd8tcell but mainly Cd4Tcell
After Naïve tcell exposure to nonself antigens presented on APC and the 3signal activation take place.. secretion of cytokines occurs
Th17 and treg share the same pathway
Cytokines like IL6 and mtor signal favor Th17 pathway but IL2 and TGF beta favor treg pathway.
What is the proposed mechanism(s) of induction of tolerance by Treg?
Contact dependent treg express cd28 on its surface and interact with cd28 on conventional tcell preventing signal 2
None contact dependent by secretion of IL10 and TGF beta which influence inhibitory effect on adaptive immunity
How would you implement Treg monitoring in clinical transplantation?
There’s is multiple markers on treg but foxp3 is the most reliable one
Is transcription factor which important for treg expression and maintain treg phenotyping and its mutation associated with autoimmune diseases
According to markers(foxp3,Cd45Ra) expressed by treg its divided to 3types
Resting treg Cd45Ra +ve,foxp3 +ve
Activated treg cd45Ra -ve , foxp3+ve
Tr1 cd45Ra-ve, foxp3-ve
Reference:
Schmidt JV, Han JM, Macdonald KG, et al. The role of FOXP3 in regulating immune responses. Int Rev Immunol 2014;33:110-128
Trzonkowski P, Dukat-Mazurek A, Bieniaszewska M, Marek-Trzonkowska N, Dobyszuk A, Juscinska J, et al. Treatment of graft-versus-host disease with naturally occurring T regulatory cells. Biodrugs. (2013) 27:605–14.
Nazik Mahmoud
3 years ago
Treg is one of CD4 T lymphocytes, generated in the thymus by exposure to self antigen .
Has a role in the T cell suppression by cytokines like IL-10 and by inhibtory membrane molecules like CTL-4.
It lead to peripheral tolerance .
High level of Treg prevent the rejection so we need to keep it high. They express the Foxp3 which indicates their activity and we can monitor them by measuring it.
It found to be had a great role in treating cancers and autoimmune disease
Dear Nazik Thank you for your contribution You could have expanded on the subtypes of Treg and the effect of immunosuppression on the Treg population. You need to write with references.
Tahani Hadi
3 years ago
Treg have a role in regulating and suppressing of the immune system Treg characterized by expression of both Cd4 T cells and CD 25 also expression of nuclear transcription factor FoxP3 ,their supprissive activity is achieved by contact dependent and independent mechanisms ,both simultaneously cause suppression of effector T cells through different Ag specificities or effect on T cells tolerance that recognize Ag also by effecting on CD4+ ,CD8+ T cells ,B cells macrophages dendritic cells and memory cells .
Different medications effect on Treg action either by inhibition or activation and increase survival :calcineurin inhibitorscause decrease proliferation and viability ,MMF variable effect ,steroid no effect on Treg activity ,mTOR inhibitors help to differentiation and proliferation and increase FoxP3 expression, using of alemtuzumab in induction help to generation and expansion of Treg while using of anti CD25(basiliximab) have adverse effect on Treg because of high expression of CD 25 on Treg also using low dose of recombinant IL-2 have dramatic effect on Treg expansion finally there are non immunosuppressive medications have effect on Treg like metformin cause increase Treg and erythropoietin effect on their proliferation also effect on T cells proliferation.
When tolerance occurs by the effect on Treg it should be monitored by different ways like,flow cytometry,programmed graft biopsy and DSA monitoring.
CD4+ T cells are divided into regulatory T cells & conventional T helper cells. T helper cells control adaptive immunity against pathogens and cancer by activating other effector immune cells. regulatory T cells are defined as CD4+ T cells that suppress or regulate the effect of helper cells. ın other words Treg is a subgroup of suppressor T cells. although not specific to it, there are some markers for Treg cells. The most widely used markers for Treg cells are CD25, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR), lymphocyte activation gene-3 (LAG-3), CD127, and forkhead/winged-helix transcription factor box P3 (Foxp3). Their main effector cytokines include IL10, TGF-β, and IL35. IL10 has a potent inhibitory effect that suppresses pro-inflammatory response thereby limiting tissue damage initiated by the inflammatory process. the specific markers of thymic (tTreg) and peripheric (pTreg) are not well defined.
Recently, (Treg)s have been shown to suppress most immune cell types, including lymphocytes, various types of macrophages, dendritic cells, and also B cells. they have a very heterogenous proposed mechanism that may clarify their impressive effect on the effector cells though well not clearly identified. by expression of the inhibitory
molecule TIGIT they also inhibit Th1- and Th17-mediated pro-inflammatory immune
response .
I a small study in 2008 ( 10.1111/j.1600-6143.2008.02268.x.) FOXP3 was associated with rejection and unfavorable outcomes. but as this is not unique to Treq, this is still not clear
A. Regulatory T cells (Tregs) are a subset of CD4+ T cells that express the transcription factor Foxp3 and potently suppress many immune responses. It has been shown that Tregs are able to inhibit T cell proliferation and cytokine production and play a critical role in preventing autoimmunity. Different subsets with various functions of Treg cells exist. Dysregulation in Treg cell frequency or functions may lead to the development of autoimmune disease.
B. Self-tolerance is a state of unresponsiveness to self-tissues/antigens.Foxp3 + T-regulatory cells (Tregs) play an essential role in suppressing autoimmune responses directed against self-antigens and thereby regulate self-tolerance. “Natural” TREG comes directly from the thymus and helps maintain self-tolerance. Natural Tregs are differentiated in the thymus on the basis of their higher TCR-affinity to self-antigens and migrate to the periphery where they maintain peripheral tolerance. In addition, extra-thymic differentiation of induced Tregs can occur in the periphery which can control abrupt immune responses under inflammatory conditions. A defect in Treg cell numbers and/or function is found to be associated with the development of autoimmune disease in several experimental models and human autoimmune diseases.
C. Augmentation of Tregs has been shown to be beneficial in treating autoimmunity in preclinical models, and Treg-based cellular therapy has shown initial promise in clinical trials. The 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.
Reference:
1. Kondĕlková K, Vokurková D, Krejsek J, Borská L, Fiala Z, Ctirad A. Regulatory T cells (TREG) and their roles in immune system with respect to immunopathological disorders. Acta Medica (Hradec Kralove). 2010;53(2):73-7.
2. Kumar P, Saini S, Khan S, Surendra Lele S, Prabhakar BS. Restoring self-tolerance in autoimmune diseases by enhancing regulatory T-cells. Cell Immunol. 2019 May;339:41-49.
3. 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
What is the proposed mechanism(s) of induction of tolerance by Treg?
Tolerance is achieved once T reg out-number T effectors .normal T reg represent 5-10% of circulating t cells. This needs to be increased up to 33% to prevent rejection.2
T reg have many mechanism for suppression of immunity :1
1- Suppressive cytokines production like IL-10, TGF-β, and IL-35
2- Inhibit the maturity of denderitic cells and production of kynurenin
3- Secretion of granzymes which are cyto-lytic of T eff
4- Through CD39&CD73 catalyze the production of inhibitory adenosine
5- Through CD25 , catch IL-2 which is the growth factor of Teff
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- Vaikunthanathan T, Safinia N, Boardman D, Lechler RI, Lombardi G. Regulatory T cells: tolerance induction in solid organ transplantation. Clin Exp Immunol. 2017 Aug;189(2):197-210. doi: 10.1111/cei.12978. Epub 2017 May 25. PMID: 28422316; PMCID: PMC5508315.
T reg
T reg are suppressor CD4 T lymphocytes with high expression of both CD25 and transcription factor FoxP3. They are either natural T reg (thymus derived )or induced peripheral Tregs
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 .
T reg can be activated through TCR in response to
1- antigenic stimulation both self and non self antigens
2- Non antigenic stimulation in response to various cytokines
T reg are involved in maintaining tolerance via recognizing , suppressing or even eliminating allo- reactive cells . First , T reg are activated by stimulation of TCR via certain Ag ,then they start to recognize the allo-reactive cells against this certain Ag and they suppress both CD4+ and CD8 + T cells in non specific way (not only to this Ag but to other Ag specific cells also ) (1)
Till now , the most reliable marker for monitoring T reg is the transcription factor FOXP3. The levels of intragraft, prepheral and urine FOXP3 mRNA in transplant recipient suffering from DGF and acute rejection where significantly elevated , so FOXP3 represents a good marker for T reg activity but it also can be expressed also in nonregulatory T-cells upon activation. Also the number of Intragraft Treg appears to indicate graft rejection . Other markers to identify Treg including CD45RB , CTLA-4 , GITR , CD122, CD103, and galectin-10 and the absence of CD127 , are still underinvestigations.(2)
1- Hu, M., Wang, Y. M., Wang, Y., Zhang, G. Y., Zheng, G., Yi, S., O’Connell, P. J., Harris, D. C., & Alexander, S. I. (2016). Regulatory T cells in kidney disease and transplantation. Kidney international, 90(3), 502–514. https://doi.org/10.1016/j.kint.2016.03.022
2- Brown K and Wong W (2009). Monitoring Regulatory T-Cells after Transplantation: Is It Useful?.
Trends in Transplant ;3:119-28
Hinda Hassan
3 years ago
What is Treg and how it is activated?
T reg are part ofCD4+T lymphocytes which concern of suppressing other t cells. It has role in prevention of autoimmune diseses . in transplantion, upregulation or infusion of t cell is supposed to be associated with induction of tolerance. 1
Activation of t reg occur through stimulation of either : CD3 and CD28 molecules or alloantigenic expressing APC. This stimulation require IL2 and rapamycin.1
T reg have TCR which when activated produce several molecules like IL-10, IL-35, TGF-β, and cAMP; expression of c oenzymes CD39 and CD73which will degrade ATP and kill APC.2
1-Edozie et al ,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-Qizhi Tang, Flavio Vincenti, Transplant trials with Tregs: perils and promises,J Clin Invest. 2017;127(7):2505-2512. https://doi.org/10.1172/JCI90598.
MICHAEL Farag
3 years ago
What is Treg and how it is activated?
regulatory T cells (also called Tregs) are T cells which have a role in regulating or suppressing other cells in the immune system. Tregs control the immune response to self and foreign particles (antigens) and help prevent autoimmune disease. Tregs produced by a normal thymus are termed ‘natural’; nTreg. Treg formed by differentiation of naïve T cells outside the thymus, i.e. the periphery, or in cell culture are called ‘adaptive’ or inducible ; iTreg. Natural Treg are characterised as expressing both the CD4T cell co-receptor and CD25, which is a component of the IL-2 receptor. Treg are thus CD4+ CD25+. Expression of the nuclear transcription factor Forkhead box P3 (FoxP3) is the defining property which determines natural Treg development and function. FoxP3 is crucial for maintaining suppression of the immune system. Naturally occurring mutations in theFOXP3 gene can result in self-reactive lymphocytes that cause a rare but severe disease IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked) in humans and scurfy in mice. Tregs suppress activation, proliferation and cytokine production of CD4+ T cells and CD8+ T cells, and are thought to suppress B cells and dendritic cells. Tregs can produce soluble messengers which have a suppressive function, including TGF-beta, IL-10 and adenosine. Additional markers of natural Tregs are CD152 (CTLA-4) and GITR (glucocorticoid-induced TNF receptor), although it should be noted that these are also expressed by other T-cell types periodically (e.g. activated T cells) so they are not in themselves unequivocally diagnostic. However, the role of these markers on other T cells is not clearly defined[1] The activation of Treg cells is antigen-specific, which implies that the suppressive activity of Treg cells is triggered in an antigen-specific fashion. A major challenge for the Treg field is to understand how Treg cells discriminate between the bad (i.e. self-reactive) Th cells, which should be suppressed, and the good (i.e. virus-specific) Th cells, which should not. If this distinction is not made, the host will be immunosuppressed and succumb to microbial infection or cancer. Upon antigen exposure in the regional lymph nodes, Foxp3+ Tregs become activated and exert suppression at a much lower concentration of antigen than naive T cellsTreg cells are suggested to be autoreactive and to suppress conventional Th cells with the same antigen specificity. This allows Treg cells to mediate natural tolerance by ensuring self/non-self discrimination. The mechanism of suppression is proposed to be based on a three-partner interaction between the Treg cell, the Th cell to be suppressed, and the antigen-presenting cell (APC)[2]
What is the proposed mechanism(s) of induction of tolerance by Treg?
Blocking costimulatory pathways can induce allograft tolerance in major histocompatibility complex (MHC) mismatched kidney transplant models. Recent studies showed that Foxp3+ Tregs were activated by blockade of B7-CD28 and CD40-CD40L pathways. In primates, the combination costimulatory blockade with CTLA4-Ig and anti-CD40L, anti-CD40 and anti–B7-2, or anti-CD40L, sirolimus, and a single donor-specific transfusion can significantly prolong renal allograft survival across an MHC mismatch.[3] low-dose IL-2 therapy has been shown to selectively expand FOXP3
How would you implement Treg monitoring in clinical transplantation?
the frequency of Tregs was measured with flow cytometry other method was used is measuring Il-10 secretion by ELISA monitoring of circulating Tregs in peripheral blood is helpful for evaluating the immune status of kidney transplant recipients during the early post-transplant period, hence, it can be helpful for choosing immunosuppressive regimen [4]
Treg is a subset of CD4+ T cells having regulatory or immunosuppressive actions. (1) They maintain immunological balance by providing immune tolerance against self-antigen and keeping immune reactions under control.
Treg activation is antigen dependent. The T cel receptor (TCR) engagement of the Treg by antigen leads to immune response suppression.
What is the proposed mechanism(s) of induction of tolerance by Treg?
There are multiple mechanisms of action of Treg, (2) These include:
a) Contact-independent anti-inflammatory cytokine (IL-10, IL-35 and TGF beta) production, and exosome formation leading to specific gene silencing, ultimately preventing T cell activation.
b) Contact dependent suppression through interaction of CTLA4 on Treg with CD80/86 on APC, restricting T cell access to signal 2 (due to higher affinity of CTLA4 than that of CD28).
c) Inducing apoptosis using Fas/FasL and Granzyme/perforin pathways.
d) Disruption of metabolic pathways via CD39, causing decreased ATP triggered proinflammatory signals. Tregs have increased intracellular cAMP which gets transferred to T effector cells leading to increased ICER (inducible cAMP early repressor), inhibit IL-2 transcription leading to low IL-2 causing apoptosis.
The CD8+ T cells are responsible for graft destruction by apoptosis due to cytotoxic activity.
How would you implement Treg monitoring in clinical transplantation?
Tregs can be monitored in clinical transplantation by the specific markers related to Treg including FOXP3, CD25, CTLA4, GITR and CD127. (3) These markers are T cell activation markers, hence they are not specific for Treg.
Tregs have been used in clinical trials in transplantation as a way to induce tolerance. Deuterium labelled pTregs have been used in kidney transplant recipients. (4) Post transfusion, these could be tracked by their deuterium signals. Similarly, Indium labelled T regs have also been transfused in kidney transplant recipients and monitored using SPECT. (5)
References:
1) Issa F, Schiopu A, Wood KJ. Role of T cells in graft rejection and transplantation tolerance. Expert Rev Clin Immunol 2010;6:155-169.
2) Vaikunthanathan T, Safinia N, Boardman D, et al. Regulatory T cell: tolerance induction in solid organ transplantation. Clin Exp Immunol 2017;189:197-210. 3) Corthay A. How do regulatory T cell work? Scand J Immunol 2009;70:326-336. 4) Chandran S, Tang Q, Sarwal M, et al. Polyclonal regulatory T cell therapy for control of inflammation in kidney transplants. Am J Transplant 2017;17:2945-2954. 5) Hutchinson JA, Riquelme P, Sawitzki B, et al. Cutting Edge: Immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients. J Immunol 2011;187:2072-2078.
have been shown to be important in maintaining immune homeostasis and preventing autoimmune disease, including autoimmune kidney disease. It is also likely that they play a role in limiting kidney transplant rejection and potentially in promoting transplant tolerance. Although other subsets of Tregs exist, the most potent and well defined Tregs are the Foxp3 expressing CD4+ Tregs derived from the thymus or generated peripherally.
Are a subset of CD4+ T cells that express the transcription factor Foxp3 and potently suppress many immune responses.
There are more than 1 type
_ NATURAL : express CD 25
_ INDUCABLE :
Tregs are activated by expression of the transcription factor FoxP3, which appears to be a “master” gene for the development and function of this type of T LYMPHOCYTE.
● Establishing tolerance to an allograft has become an area of intense study and would be the ideal therapy in clinical practice.
The discovery of a subset of T cells naturally committed to perform immunoregulation has led to further investigation into their role in the immunopathogenesis of transplantation.
Evidence suggests that regulatory T cells (Tregs) are fundamentally involved in promoting allograft tolerance.
Efforts to characterize specific markers for Tregs, while challenging, have identified Foxp3 gene expression as a crucial step in promoting the tolerance inducing features of Tregs.
●●●
MONITORING BY:
CD4+CD25+ και CD4+CD25+FoxP3+ Τ lymphocytes CAN BE measured, by flow cytometry
BEFORE renal transplantation & after it by 3 months.
September 2020 – Volume 104 – Issue S3 – p S311
doi: 10.1097/01.tp.0000700084.83497.0e ●●●●●●●●●●●●●●
Some EXTRA information about TREG :
● Tregs are important in countering the development of allergic and autoimmune disease, as FoxP3 mutant mice and humans develop airway inflammation, eosinophilia, and elevated serum IgE levels.
●Tregs have also been implicated in the prevention of graft rejection and graft versus host disease (GVHD
☆☆The discovery of a subset of T cells naturally committed to perform immunoregulation has led to further investigation into their role in the immunopathogenesis of transplantation.
☆☆Organ transplantation is considered the ultimate therapy for end-stage organ disease.
While pharmacologic immunosuppression is the mainstay of therapeutic strategies to prolong the survival of the graft, long-term use of immunosuppressive medications carries the risk of organ toxicity, malignancies, serious opportunistic infections, and diabetes.
●Therapies that promote recipient tolerance in solid organ transplantation are able to improve patient outcomes by eliminating the need for long-term immunosuppression.
●●●●●●●
FURTHER INFORMATION ABOUT TREG:
A number of approaches, including those based on targeting the glycogen synthase kinase 3β signaling pathway or activating the melanocortinergic pathway, have been tested as a way to promote Treg lineage commitment and maintenance as well as to facilitate immune tolerance.
In order to be effective in clinical practice, Tregs must be allospecific and possess a specific phenotype to avoid suppression of other aspects of the immune system or increasing the risk of malignancy or infections.
Multiple experimental and clinical studies have demonstrated the impact of currently used immunosuppressants on the immunoregulatory activities of Tregs and their Foxp3 expression status.
Pharmacological induction of tolerogenic Tregs for inducing transplant tolerance, including epigenetic therapies, is in the ascendant.
—-> Therapies that promote Treg function and survival may represent a novel strategy for achieving immune tolerance in transplant patients <—-
Last edited 3 years ago by Mina Meshreky
Wessam Moustafa
3 years ago
Treg are specialized T cells ( Subtype of CD4 T cells ) that inhibit deleterious immune response of the conventional T helper cells as they prevent T cell proliferation and cytokine production .
They help to maintain homeostasis and tolerance
**Functions of T regs include :
1.Prevention of autoimmune diseases by maintaining immunologic self-tolerance .
2.Suppression of allergy and asthma .
3.Induction of tolerance against dietary antigens ( oral tolerance )
4.Induction of maternal tolerance to the fetus
5.Suppression of pathogen-induced immunopathology .
6.Regulation of the effector class of the immune response .
7.Suppression of T-cell activation triggered by weak stimuli .
8.Feedback control of the magnitude of the immune response by effector Th cells .
9.Protection of commensal bacteria from elimination by the immune system .
** activation of T regs occurs through antigen specific manners , and so their suppressive effect on T helper cells is antigen dependent
Whether the same antigen activates both T helper and TRegs or not , it is believed that T regs can suppress T helper cells of different antigenic specificities , but it’s effect is more potent and relevant when both have same antigen specificity .
during maturation in the thymus gland , Treg cells would be generated with a high affinity TCR for a self peptide.
And so they are self reactive and help to suppress immune response to self antigens and maintain tolerance
An important discovery in the field of Treg therapy in humans is the finding that Tregs can be isolated and expanded in vitro while maintaining immunoregulatory function.
Studies showed that infusion of Tregs has the potential to induce long-term donor-specific tolerance without interfering with immune responses to pathogens and tumors in transplant patients.
Treg therapies have proved efficacy in alloimmune responses in the settings of graft-versus-host disease (GvHD), as well as organ and cell transplantation in animal models.
Molecular markers of Treg markers include : CD25, CTLA-4, GITR, CD127, LAG-3 and Foxp3
There is growing evidence that all of the appear to be general T-cell activation markers.
This observation strongly suggests that T-cell activation is required for T-cell mediated suppression.
One of the critical functions of the immune system is to prevent responses directed toward self-antigens. It is achieved during two processes, central (in the thymus) and peripheral (extrathymic lymphoid tissue) tolerance. Treg in humans are CD4+ T lymphocytes that express high levels of CD25 and the transcription factor FOXP3. It is now clear that FOXP3 does not function alone and that other molecular mechanisms such as DNA epigenetic modification and expression of additional transcription factors are required to induce highly stable, functional Tregs.
Mechanisms of tolerance were described as recessive tolerance and dominant tolerance. Recessive tolerance mechanisms depend on clonal deletion and anergy. The term recessive refers to the fact that all self-reactive T cells need to be physically eliminated or functionally inactivated. In contrast, dominant tolerance depends on suppressive action of regulatory cells and can therefore be transferred from tolerant to naïve individuals.
It is illustrated that elimination of CD25+FOXP3+ CD4+ T cells (Treg) unleashed a latent autoimmune potential in the normal T cell repertoire. Approximately 80% of Treg cell repertoire originate from the thymus (thymus derived Treg cells) where FOXP3+ Treg cell differentiation can be instructed by encounter of agonist self-antigens. Thus, recognition of self during thymocyte differentiation not only leads to clonal deletion, but also specifies diversion of cells into self-reactive T cell lineage that lacks autoimmune potential, and instead confers tolerance through immune regulation. Simple models that explain different outcomes of self-antigen recognition in the thymus are based on the affinity and/or avidity of the underlying TCR-peptide-MHC complex interactions. T cell signals crucially impact the cell fate decisions of thymocytes.
The term affinity describes the strength of a single interaction between TCR and it’s peptide-MHC ligand, where as the term avidity is proportional to the multiplicity of such interactions.
According to an affinity-based model of thymocyte development, at a given fixed density of cognate peptide-MHC in the thymus, T cells bearing the highest affinity TCRs are removed from the repertoire by clonal deletion, whereas T cells bearing TCRs of intermediate affinity are diverted into Treg cell repertoire. T cells bearing TCRs of low affinity escape into the periphery as conventional T cells (at a fixed level of neo-self-antigen expression, the efficiency of Treg cell selection was directly correlated with the reactivity of different TCRs).
An avidity-based model posits that in addition to the TCR affinity, the density of the peptide MHC ligand is also crucial. At a given fixed TCR affinity, increasing or decreasing the density of antigen presented on thymic antigen-presenting cells will lead the cell fate towards either clonal deletion or Treg cell differentiation, respectively. Several observations are consistent with this model. First, TCR-transgenic models have shown a clear correlation between antigen expression levels and the ensuing cell fate. Second, the titrated administration of agonist peptide to TCR-transgenic fetal thymic organ cultures or through intravenous injection into adult mice revealed a positive correlation between agonist concentration and the number of Treg cells; above a certain threshold, further increasing the peptide dose resulted in thymocyte deletion. Third, at fixed levels of antigen expression, attenuating cognate antigen presentation through the knockdown of MHC class II expression resulted in decreased clonal deletion and increased emergence of Treg cells. Finally, low-affinity or high-affinity peptide ligands for the same TCR can instruct Treg cell differentiation with equal efficiency provided that the density of the low-affinity ligand is correspondingly higher.
The process of negative selection (deletion of T lymphocyte with undesirable activity) is not perfect in the thymus, and the autoreactive T lymphocytes, which escape from negative selection, can be found in the periphery and prevented by the process of peripheral tolerance. The process of peripheral tolerance and regulation can lead to the generation of regulatory T cells (induced or peripheral Treg).
Regulatory lymphocytes suppress autoimmune reaction and prolong allograft survival. They suppress immune responses by different mechanisms including cytokines (IL 10, TGF β) and inhibitory membrane molecules (CTLA-4), and by the release of adenosine through the CD39-CD73 pathway.
Several studies in kidney transplantation have shown a positive correlation between the presence of Treg cells and good clinical outcome.
The role of Treg cells in the prevention of graft rejection and the induction and maintenance of allograft tolerance is clearly demonstrated. The presence of intragraft FOXP3 Treg cells was associated with an overall donor-specific hyporesponsiveness of T cells toward alloantigens and expansion of peripheral CD25+FOXP3+ T reg in patients and as well as favorable graft outcome.
The reports also demonstrated higher frequencies of circulating Tregs in tolerant patients. Interestingly, an increase in mTregs was found uniquely in operationally tolerant patients compared to other transplant recipients and healthy donors.
Expanding the Treg population and shifting the immune balance in favor of the regulatory cells has been proposed as a strategy to potentially minimize the need for effector immunity control, reduce immunosuppression requirements, and induce tolerance. In small animal studies, CD4+CD25+FoxP+Treg have been infused to effectively prevent acute and chronic rejection.
The studies that introduced protocols for mixed chimerism have demonstrated that combined kidney and stem cell transplantation using an engineered cellular product enriched in hematopoietic stem cells and tolerogenic graft facilitating cells was able to promote graft tolerance in mice by increasing Tregs.
Another important aspect of Tregs in human kidney transplantation is the influence of immunosuppressive treatment. An increase or decrease in circulating/intragraft Tregs could be the consequence of certain suppressive therapies. About CNIs, they provided conflicting results. Some studies have shown negative effects of CNIs on the expression of Treg cells and others have demonstrated enhancement of Treg function using clinically relevant doses of CNIs. It seems that these discrepancies may be due to different dose-dependent effects of the drugs. In contrast to CNI, inhibitors of the mTOR pathway are well-established pro-Treg factors, and can increase and stabilize Treg phenotype and suppressive functions, notably by maintaining a complete demethylation of FOXP3.
Ludger Klein1*, Ellen A. Robey2 and Chyi-Song Hsieh3. Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation, NATuRe RevIewS | IMMunology, volume 19 | JANUARY 2019
F. Braza1,2,3, M. Durand1,2,3, N. Degauque2,3 and S. Brouard, Regulatory T Cells in Kidney Transplantation: New Directions? American Journal of Transplantation 2015; 15: 2288–2300
Nahel Elias, A. Benedict Cosimi, and Tatsuo Kawai, Clinical trials for induction of renal allograft tolerance, Curr Opin Organ Transplant 2015, 20:406–411
Professor Ahmed Halawa
Admin
3 years ago
Dear All
What is the relation between Treg and acute rejection?
Treg are the T cells responsible for immune response suppression. Hence in the clinical situation with low Treg, there is high chance of acute rejection.
High level of Treg prevent rejection because it suppress the immune response
Assafi Mohammed
3 years ago
Treg
Tregs are CD4+CD25 high T lymphocytes expressing FoxP3 transcription factor either constitutively (thymic Tregs or tTregs) or after peripheral recognition of antigens (peripheral Tregs or pTregs).
RoleofTregs In addition to their (i) role in self-antigen tolerance, both Treg subsets can (ii) suppress inflammatory alloreactive T cells in vitro and in vivo.They(iii) inhibit alloreactivity in MLR in vitro and are thought to (iv) mediate transplant tolerance elicited via leukocyte costimulation blockade, donor-specific transfusion.
Proposed mechanism(s) of induction of tolerance by Treg :
tTregs are positively selected in the thymus medulla based on their high affinity for self-antigen pMHC complexes While tTregs require TCR interaction with self-MHC class II molecules to mediate their suppress functions, they are thought to be non-antigen specific. Indeed, tTregs isolated from native mice can suppress T cells responding to polyclonal stimulators (anti-CD3/anti-CD28 mAbs or PMA/ionomycin) and MLR regardless of the nature of the allogeneic stimulators.
Inoculation of Tregs from tolerant mice to native mice could prolong allograft survival and even transfer tolerance. In addition, studies from Colvin’s laboratory using FoxP3-diphtheria toxin receptor mice showed that in vivo deletion of Tregs abrogated ongoing tolerance to kidney allografts in mice .
The nature of the self-peptide determinants recognized for tTregs is not known. Studies from LeGuern’s laboratory suggest that tTreg recognition is biased to self-MHC class II peptides bound with self-MHC class II molecules themselves (referred to as Tlo){LeGuern C. Regulation of T-cell functions by MHC class II self-presentation. Trends Immunol (2003) 24(12):633–8. doi:10.1016/j.it.2003.10.010}. Tolerance of solid organ transplants in swine and rodents via allo-MHC class II transgenesis support this view .
In contrast to tTregs, pTregs presumably acquire FoxP3 expression and suppressor functions through recognition of donor antigens (MHC and/or minor antigens) presented by selected APCs (immature DCs and plasmocytoid DCs) in an appropriate cytokine milieu .
Although activation of pTregs may be antigen specific, it is not clear whether their suppressive function follows the same rules. Therefore, both Treg subsets involved in allograft tolerance are presumably activated through recognition of peptides presented by self-MHC class II on recipient APCs, i.e., in an indirect fashion. However, the mechanisms by which they suppress alloreactive T cells and induce and/or maintain allograft tolerance are still unknown.
Implementation of Treg monitoring in clinical transplantation:
The importance of regulatory T-cells (Treg) in tolerance models makes their surface or intracellular markers obvious candidates to provide a biomarker for transplantation.Unfortunately, a definitive marker for Treg in humans is yet to be found.
Application of cell-based immunotherapy in organ transplantation to minimize the burden of immunosuppressive medication and promote allograft tolerance has expanded significantly over the past decade.{Front. Immunol., 14 December 2020 | https://doi.org/10.3389/fimmu.2020.614578 Detection and Monitoring of Regulatory Immune Cells Following Their Adoptive Transfer in Organ Transplantation}.
The classic Treg are enriched within the CD4+CD25+ T-cell population. To date, the most reliable marker available is forkhead box p3 (FOXP3), a member of the forkhead/ winged helix family of transcription factors. In mice, Foxp3 is a specific marker of Treg , however in humans this transcription factor is also transiently expressed in nonregulatory T-cells upon activation. Other markers used to identify Treg include CD45RB CTLA-4, GITR, CD122, CD103, and galectin-10, and the absence of CD127 can also indicate a regulatory phenotype. A combination of these markers may be the best way of identifying Treg.
Doaa Elwasly
3 years ago
– What is T reg ?
T regulatory cells are a specified subpopulation of T cells which suppress immune response, so that homeostasis and self-tolerance are maintained .(1)
Tregs are divided in subpopulations according to the differentiation sites and the expression of functional markers, inspite of this there is overlap between these parameters. (2)
– how it is activated?
In the thymus, thymically derived Treg( tTregs,) are developed serving as an insurance to prevent self-autoreactivity
Foxp3 is the lineage-specifying transcription factor of Tregs, whose deficiency can cause fatal autoimmune disease.
Rudensky et al mentioned that the conserved noncoding sequence (CNS)1 of the Foxp3 gene, is critical for the generation of induced press but dispensable for tTreg development.
Precautions must be taken to ensure the identity and stability of Tregs for translation in clinical use although it has great therapeutic potential for curing autoimmune diseases and preventing unwanted immune responses such as graft-versus-host disease.(3)
tTregs and induced T reg (iTregs) play different roles in different tissues. iTreg differentiation induced by non-self- antigens and a particular TCR signaling combined with other signals ,these cells are more functional for maintaining mucosal tolerance. iTregs may control immune responses to commensal antigens and prevent allergic-type reactions.(2)
-Induction of tolerance ?
Tregs regulate immune responses and tolerance in multiple ways,
possibly Tregs have a memory phenotype expressing high levels of effector memory markers, including IL-7R (CD127), CD44, and CD27 . (3)
Tregs elicit a direct response on a target cell, or indirect, in which a third-party cell is affected and suppresses the target cell .
Tregs can influence changes in the microenvironment due to expression of CD25, this receptor in high levels enables it to uptake more IL-2 and “starve” the surrounding cells of this cytokine.
Also NKs is directly affected by Tregs in a membrane bound TGF-ß dependent manner. Tregs have a direct effect on B-cells via PDL1/PD-1 interaction and DCs.
Tregs suppress CD4 T cell activation and proliferation by contact-dependent and contact-independent mechanisms .
Tregs can also influence proliferation, activation and apoptosis of CD8+ T cells.(2)
-T reg in transplanation?
The possibility of Treg isolation, expansion and infusion in kidney transplant recipients on immunosuppression with subclinical graft inflammation was tested . Three kidney transplant recipients were enrolled They received a single infusion and were maintained on tacrolimus, mycophenolate mofetil and prednisone and they were followed ,The authors showed that infused Tregs peaked in circulation the first week which were detectable during the first month after infusion ,dropping near the detection limit at 3 monthsafter wards with no increased incidence of infection nor malignany within 1 year of follow up but referring to the low number of the included patients, it was not possible toexpress any conclusion of either safety or efficacy of Treg infusion isolated from kidney transplant recipients.
Multiple clinical trials using Tregs to prevent rejection in solid organ transplantation are still going on and results are pending, but some studies demonstrated preliminary the capability of Tregs to treat autoimmune diseases and prevent graft rejection. In fact it will take time for it to be implemented in practice .(2)
1-Kondelkova K et al.Regulatory T cells (TREG) and their roles in immune system with respect to immunopathological disorders .Acta Medica (Hradec Kralove)2010;53(2):73-7.
2- Romano M.etal al .Past, Present, and Future of Regulatory T Cell Therapy in Transplantation and Autoimmunity .Front. Immunol., 31 January 2019.
3-Zhang Z etal . Activation and Functional Specialization of Regulatory T Cells Lead to the Generation of Foxp3 Instability .J Immunol 2017; 198:2612-2625.
Alyaa Ali
3 years ago
Treg cells
Regulatory T cells (Treg) are a subset of CD4+ T cells which have a role in regulating or suppressing other cells in the immune system. they control the immune response to self and foreign antigensand help prevent autoimmune disease.
they express both the CD4 T cell co-receptor and CD25, which is a component of the IL-2 receptor and express the transcription factor forkhead box P3 protein (FOXP3)
The activation of Treg cells is antigen-specific
Treg can generated either in thymus during negative selection(natural Treg) or in the periphery (induced Treg cells).
Two main subsets of iTregs that are generated in the periphery based upon the cytokines that cause their induction: type 1 regulatory T cells (Tr1), which are induced by IL-10 , and T helper 3 (Th3), which are induced by TGFβ . While both subsets are generated in the presence of different cytokines, they exert their suppressive activity through secretion of the same cytokines that are responsible for their induction, IL-10 and/or TGFβ, respectively. While TGFβ and IL-10 are the primary cytokines involved in iTreg formation, it has also been demonstrated that IL-4 and IL-13 can induce the development of Foxp3+ Tregs from Foxp3− naïve T cells independently of TGFβ and IL-10 .
Regulatory T cells are major contributors to peripheral tolerance:The immune system uses many mechanisms to maintain immunologic self-tolerance and protect the host against exacerbated responses to foreign antigens. The existence of regulatory T cells [Tregs] that actively suppress the function of conventional T cells is a key mechanism by which the immune system limits inappropriate or excessive responses.
Tolerance is a state of unresponsiveness in which the lymphocytes remain alive but cannot exert effector functions against a particular antigen. There are two types of tolerance:
central tolerance:by deletion of lymphocytes that have receptors specific for self-antigen in thymus then the other lymphocytes ( Lymphocytes that do not receive survival signals undergo apoptosis and those receive the correct antigen signals will leave the thymus and circulate in the periphery).Some CD4+ T cells receive signals in the thymus that select them to differentiate into natural Treg.
peripheral tolerance:When self-reactive T cells escape into the periphery, peripheral tolerance ensures that they are deleted or become anergic (functionally unresponsive to antigen).
Mechanisms of peripheral tolerance:
1.Induction of anergy(a state of inactivation in which the lymphocytes remain alive but are unable to respond to antigen).
Example: If dendritic cells are not appropriately activated and present self-antigen to T cells without signals 2 and 3 (costimulation and cytokine signals), they will produce T cells that are tolerant or anergic to that self-antigen.
2.Deletion of autoreactive T cells via apoptosis.
3.Development of induced regulatory T cells (Tregs) which have similar effector functions as natural T regulatory cells, but they are produced in the periphery rather than in the thymus.
Flow cytometric analysis can detect Tregs in peripheral blood, spleen, draining lymph nodes (LN) and allograft tissue.
Malhotra, Deepali; Linehan, Jonathan L. Tolerance is established in polyclonal CD4+ T cells by distinct mechanisms according to self-peptide expression patterns. Nature Immunology.2016: 17 (2): 187–195.
Cretney, Erika; Kallies, Axel; Nutt, Stephen L. “Differentiation and function of Foxp3+ effector regulatory T cells”. Trends in Immunology.2013: 34 (2): 74–80.
Workman CJ, Szymczak-Workman AL, Collison LW, Pillai MR, Vignali DA. The development and function of regulatory T cells. Cell Mol Life Sci. 2009;66(16):2603-2622.
Corthay A. How do regulatory T cells work?. Scand J Immunol. 2009;70(4):326-336.
Last edited 3 years ago by Alyaa Ali
Shereen Yousef
3 years ago
What is Treg and how it is activated?
Treg cells are subtype of T lymphocytes responsible for regulation and adjustment of immune response due to its ability to suppress other types of effector cells
Tregs may develop in the thymus (tTregs), as well as and peripherally (pTregs) from effector cells.
tTregs express FoxP3 constitutively and have a T cell receptor (TCR) of relatively high autoaffinity. These cells are predominant in the bloodstream and in the lymph nodes; they are mainly involved in providing tolerance to autoantigens .
Peripherally, CD4+-effector cells affected by IL-2 and TGF-β may under certain conditions begin to express FoxP3, thus becoming functional equivalents of tTregs .
Mechanism of action
Tregs have been shown to suppress most immune cells including lymphocytes, various types of macrophages, dendritic cells and B cells .
Treg suppressive activity against a specific T effector population may be associated with the expression of transcription factors typical of this subpopulation;
Tregs are believed to acquire the expression of transcription factors typical of effector cells owing to their adaptation to the immune response being polarized toward Th1, Th2, or Th17.
• expression of T-bet, a Th-1-associated transcription factor, in Tregs is related to the expression of the inhibitory molecule TIGIT, which binds CD155 to dendritic cells to increase the production of IL-10 and reduce that of IL-12 in the dendritic cell, thus inhibiting the activation of T effectors .
•Tregs with the T-bet+TIGIT+ phenotype selectively inhibit the Th1- and Th17-mediated proinflammatory immune response .
• Th2-associated transcription factor IRF-4 enables Treg expression of ICOS and CTLA-4; along with JUNB and RBPJ, it is needed to limit the Th2-mediated immune response .
•expression of the Th17-typical factor STAT3 in Tregs is closely related to the regulation of the Th17-mediated immune response and enables the expression of IL-10, Ebi3, granzyme-B, and perforin-1 genes .
•Antigen-specific suppression is mainly caused by the direct Treg–DC (dendritic cell) interaction enabled by the specific recognition of the antigen (Ag) the DC presents as part of MHC-II by Treg TCR results in inducing an Ag-specific tolerogenic dendritic cell or rendering the DC unable to present a specific antigen.
•Antigen-non-specific mechanisms include the enzymes CD39/CD73 on the Treg surface, which cause ATP to degrade to adenosine. Increased adenosine concentration in the microenvironment inhibits DC presentation of antigens and suppresses the proliferation of activated T effectors .
•Another non-specific suppression factor is the Treg production of cytokines: TGF-β, IL-10, and IL-35.They can suppress the activation and proliferation of effector T and B lymphocytes; they can also directly induce pTregs and Bregs (75–78). In addition, TGF-β and IL-10 inhibit antigenic presentation to stimulate the generation of tolerogenic dendritic cells, which in their turn enable pTreg induction .
Daniil Shevyrev and Valeriy Tereshchenko.
Treg Heterogeneity, Function, and Homeostasis.
Front. Immunol.(2020 ).
How would you implement Treg monitoring in clinical transplantation
immunosuppression that used as tacrolimus, MMF % mehtylprednisolon can affect viability & proliferation of Treg in dose dependent manner
TRACT trial
The TRACT trial utilised ex vivo expanded polyclonal Treg cells infused in a dose‐escalation manner at the end of the expansion period. this trial reported no cases of opportunistic infections or rejection after the infusion of polyclonal Treg cells in patients undergoing de novo kidney transplantation.
TASK trial
TASK trial from UCSF focussed on utilising polyclonal Treg cells to modulate subclinical inflammation in the renal allograft.
Other trials are ongoing with promising results.
Muhammad Atif, Filomena Conti.Regulatory T cells in solid organ transplantation.
Clin Transl Immunology. 2020; 9(2): e01099.
Ala Ali
Admin
3 years ago
You all agree that Tregs are CD25 +ve cells.
What is CD25?
What induction agent blocks CD25?
How this blockage of CD25 affects Treg cells and the activated T cells response?
it is alpha chain IL-2 receptor which is expressed on activated T cell and has high affinity to IL-2, and expressed on Treg cells
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.
-Natural CD25+CD4+Tregs are engaged in suppression of autoimmune disease, its depletion leads to the development of autoimmune disease in rodents. (1)
– CD25, is the α-chain of the interleukin 2 (IL-2) receptor, is expressed on activated T cellswhich could be a therapeutic target.
Murine MAbs to human CD25 were used for prevention of renal allograft rejection.
2 of them ; basiliximab (Simulect)] and daclizumab [Zenapax])—were effective as part of induction regimens to prevent organallograft rejection, and as induction therapies in organ transplantationand for treatment of established rejection.
Also a tolerance-promoting activity of anti-CD25cannot be established because CD25 is expressed on a subset of T-cells with regulatory/suppressor capacities that are critical in maintainingimmune tolerance(2)
–CD4+CD25+Tregs exhibit an anergic phenotype in vitro , failing to proliferate or produce interleukin (IL)-2 following antigen-specific stimulation, although they can stimulate vigorous antigen-dependent proliferative responses in vivo.IL-2 appears to play a crucial role in CD4+CD25+Treg development and peripheral activity.This physiologic proliferation, in response to self-antigens, may be a main part of CD4+CD25+ Treg-mediated dominant tolerance as treatment of mice with a neutralizing anti-IL-2 monoclonal antibody prevents CD4+CD25+ Treg proliferation, leading to a reduction in their number, and development of organ-specific autoimmune disease . (3)
CD25 is alpha chain IL-2 receptor present on activated T cells. IL-2 acts on this receptor leading to clonal expansion of T cells.
2. What induction agent blocks CD25?
Anti CD25 induction agents include Basiliximab and Daclizumab.
3. How this blockage of CD25 affects Treg cells and the activated T cells response?
Anti CD25 agents use leads to aberrant pro-inflammatory T cell response due to CD25+ T cell depletion. Although it has been shown that Treg cells maintain their suppressive effects even in presence of CD25 blockade.
Reference:
Huss DJ, Pellerin AF, Collette BP, et al. AntiCD25 monoclonal antibody Fc variants differentially impact regulatory T cells and immune homeostasis. Immunology 2016;148:276-286.
Fox3p is the transcription nuclear factor expressed on CD4+CD25+ Treg to induce its inhibitory immune response and it is responsible for this function of Treg so it is Treg marker
naiive CD4 cells give rise to Treg and Th17 under effect of TGF beta, IL-6, and all trans-retinoic acid , they have an opposing function, the balance between both will be affected by many factors like cytokines released from intestinal microbiome and also commensal bacteria and its metabolites…
Sara Omenetti and Theresa T. Pizarro. The Treg/Th17 Axis: A Dynamic Balance Regulated by the Gut Microbiome. Front. Immunol., 17 December 2015.
Th17 and Treg share a common pathway, medaited by TGF beta. In the presence of pro-inflammatory signals (IL-6, IL-21), CD4+ T cells give rise to Th17 cells and in the absence of proinflammatory signals, Treg formation takes place.
The balance between the 2 depends on a number of factors like TGF beta, IL-6, m-TOR signal, segmented filamentous bacteria, glycolysis, lipogenesis nudging towards Th17, while TGF beta with IL-2, CD28 signal, FOXp3 tilt the balance towards Treg.
So if the balance shifts towards Th17, it will lead to pro-inflmmatory conditons, with increased chances of rejection.
Reference:
Lee GR. The balance of Th17 versus Treg cells in autoimmunity. Int J Mol Sci 2018;19:730
Regulatory T cells (Treg )are a specialized subpopulation of T cells that act to suppress the immune response. It can inhibit T cells proliferation, cytokine production by T cells, and suppress B cells and dendritic cells.
-The most specific marker for these cells is FoxP3, which is localized intracellularly. They are either arise in the thymus (Treg) or develop from peripheral CD4+ and express both CD4 and CD25)( that convert into CD4+FOXP3+Treg as peripherally derived Treg (pTreg).
-Their activation is antigen-specific.
– Treg was identified by flow cytometry.
-Memory Tregs are more potent than naiive Tregs.
– The suppressive function of Treg include direct cell contact 1 and regulatory cytokines such as TGF-β and IL-10 .2.3
-TGF-β is a crucial cytokine in inflammatory and mediating tolerance of allograft .,4,5,6.CD25 and class II MHC are the most common markers for Treg and are essential for transferring tolerance.7,8
-Effect of currently used immunosuppressant on Treg :
-potentiate Treg expansion eg ,ATG,almetzumab
-preserve suppressive activity and prolonged survival of Treg eg, corticosteroid
-Inhibit Foxp 3 expression and suppress Treg function in vivo and vitro eg, CNI
-promote Treg survival and function and augment Treg suppressive activity in vivo and vitro eg,mTOR
-Treg numbers can be increased through a direct infusion of Tregs or by promotion of the expansion of endogenous Tregs.
-In transplantation Tregs direct infusion is commonly used.
-The excellent early outcome result and low rejection rate of Kidney transplants make it nearly impossible to test the ability of Treg to prevent rejection when delivered at the time of transplantation 9. So, it is more challenging to design informative Treg therapy trials in kidney transplantation. References
1.H. von BoehmerMechanisms of suppression by suppressor T cellsNat Immunol, 6 (2005), pp. 338-344
2. C.I. Kingsley, M. Karim, A.R. Bushell, et al.CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses J Immunol, 168 (2002), pp. 1080-1086
3. Z. Fehervari, S. SakaguchiDevelopment and function of CD25+CD4+ regulatory T cellsCurr Opin Immunol, 16 (2004), pp. 203-208
4.M. Saraiva, A. O’Garra The regulation of IL-10 production by immune cells Nat Rev Immunol, 10 (2010), pp. 170-181
5.J. Andersson, D.Q. Tran, M. Pesu, et al. CD4+ FoxP3+ regulatory T cells confer infectious tolerance in a TGF-beta-dependent manner J Exp Med, 205 (2008), pp. 1975-1981
6.W. Chen, W. Jin, N. Hardegen, et al.Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3 J Exp Med, 198 (2003), pp. 1875-1886
7. Waight JD, Takai S, Marelli B, Qin G, Hance KW, Zhang D, et al: Cutting edge: epigenetic regulation of Foxp3 defines a stable population of CD4+ regulatory T cells in tumors from mice and humans. J Immunol 2015; 194: 878–882.
8.Green DR, Flood PM, Gershon RK: Immunoregulatory T-cell pathways. Annu Rev Immunol 1983; 1: 439–463.
9. Matas AJ, et al. OPTN/SRTR 2013 Annual Data Report Kidney. Am J Transplant. 2015;15(suppl 2):1–34.
Foxp3 is a marker expressed in the Treg
And the Treg. Cells can classify to FOXp3 low expression Resting Treg while Treg cell with high FOXP3 expression. Called effector[ eTreg ] both Types Have immunosuppressive activity in vitro Also rTreg cells can proliferate and differentiated into eTreg cells after TCR activation and the eTreg are anergic and prone to apoptosis
While the CD45RA FOXP3 low expression nonTerg cells have no immunosuppressive and express the proinflammtory cytokines like IL-17,IL-2 and interferon -¥
rTreg cells have the subset of specific reprogramming to control different immune responses and it’s effect. Dynamic
One more about the importance of stability and plasticity of FOXP3 Treg cells
Some Foxp3 T cells may lose foxp3 expression and acquire effector Th cell function under certain inflammatory conditions
Adoptive transfers of Foxp3 T cells consider instable , 50% of the donor cells bacame foxp3 T cells and converted to IFN-¥ , IL 17 IL 2 producing cells
Modification. Of foxp3 are consider potential Therapeutic target for inflammation .Inhibitors of foxp3 positive regulators could be used to activate the immune system through the down regulation of the immunosuppressive activity of Treg while inhibitors for foxp3 negative regulators could be used to put brake on immune responses through. Up-regulations the immunosuppressive function of T reg cells .
References
FOXP3 regulatory T cells and their functional regulation
Cellular and molecular immunology 2015’12,558-565
Excellent response. More attention to writing style would add a lot.
Weam Elnazer
3 years ago
Regulatory T cells (Tregs) are a subset of T cells that suppress immune activation and limit autoimmunity in the periphery (7).
A number of cell types with immune-regulatory function have been characterized as Tregs, though the one best understood, at present, are the CD4+FOXP3+ Tregs. These either arise in the thymus (Tregs) or develop from peripheral CD4+ T cells that convert into CD4+FOXP3+ Tregs as peripherally derived Tregs (pTregs).
Previously, it had been thought that peripheral tolerance due to either Tregs or pTregs would be insufficient for long-standing tolerance. However, increasing understanding of Tregs and other regulatory subsets has led to the possibility that transplant tolerance allowing reduction or cessation of immunosuppression could be achieved using regulatory cell subsets.
Tregs have been studied as a potential therapeutic in human solid organ transplantation. Sixteen Treg clinical trials that have focused on feasibility, safety and preliminary efficacy of infused Tregs to reduce the dose of calcineurin inhibitor (CNI)-based immunosuppression have been reported.
However, the majority of reported clinical trials using Tregs lack the capacity to robustly identify mechanistic effects and much of our understanding of underlying mechanisms relies on extrapolation of results from rodent and non-human primate studies.
Autologous or donor-derived peripheral blood is the most common source of Tregs used in clinical trials, although alternate sources such as umbilical cord blood and paediatric thymus, non-lymphoid tissue such as skin, adipose tissue and muscle have been explored.
Peripheral blood contains only a small proportion of Tregs that require purification via CD25+ cell selection, with or without CD8+ depletion.
Ex vivo expansion of these naturally-occurring Tregs can be achieved through various means, but the choices are dependent on whether polyclonal or donor allo Ag-reactive Treg (darTreg) is required.
darTregs are theoretically more potent, however, the majority of trials have expanded polyclonal Tregs with a combination of IL-2 and anti-CD3/CD28 magnetic bead stimulation ± rapamycin or TGF-β, although this process may require a greater cell infusion dose to achieve donor-specific suppressive effects.
Spence A, Klementowicz JE, Bluestone JA, Tang Q. Targeting Treg Signaling for the Treatment of Autoimmune Diseases. Curr Opin Immunol (2015) 37:11–20. DOI: 10.1016/j.coi.2015.09.002
Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S, et al. Regulatory T Cells: Recommendations to Simplify the Nomenclature. Nat Immunol (2013) 14(4):307–8. DOI: 10.1038/ni.2554
Putnam AL, Safinia N, Medvec A, Laszkowska M, Wray M, Mintz MA, et al. Clinical Grade Manufacturing of Human Alloantigen-Reactive Regulatory T Cells for Use in Transplantation. Am J Transplant (2013) 13(11):3010–20. DOI: 10.1111/ajt.12433
“Tregs have been studied as a potential therapeutic in human solid organ transplantation. Sixteen Treg clinical trials that have focused on feasibility, safety and preliminary efficacy of infused Tregs to reduce the dose of calcineurin inhibitor (CNI)-based immunosuppression have been reported.
However, the majority of reported clinical trials using Tregs lack the capacity to robustly identify mechanistic effects, and much of our understanding of underlying mechanisms relies on extrapolation of results from rodent and non-human primate studies.”
Would you please elaborate more and add references on the therapeutic uses of Tregs?
Ban Mezher
3 years ago
CD4 T cells divided into Treg & Th cells( Treg function is to suppress dangerous activity of Th cells).In 1995 was the first time when a special phenotype of CD4 T cells in thymus (which have high level of IL-2R( CD25) & Foxp3) discovered . Since that several studies proved the importance of Treg cells in monitoring of immune homeostasis & prevention of autoimmunity. It can generated from thymus or peripheral T cells. Several functions of Treg are proposed in last decade as:
prevention of autoimmune disease( by immunological self-tolerance).
suppression of allergy.
induction of oral tolerance
induction of maternal tolerance to fetus
suppression of T cell activation triggered by weak stimuli feedback control of immune response by effector Th cells
T reg cells can suppress immune response through different mechanism:
cytokines as TGFB, IL-10 & IL-35.
granzymes & perforin which can lyse the effector cells
metabolic interruption & immunomodulation.
interaction with dendritic cells which can modulate their function & maturation.
There are different studies aimed to decrease using of immunosuppressants , so Reg cells may be good solution to control immune response & induce transplant tolerance.
In 2017 phase I pilot study was done & its aim was to test the capability of isolation, expiation & infusion of Treg cells to renal transplant recipients, but due to low number of patients the safety of the infusion of Reg is not possible. Another phase I study started in 2018 that infuse Treg cells to recipients show increase the number of Treg after infusion comparing to control group & decide to precede to phase II trial.Most of the studies that use Treg to prevent rejection in solid organ transplantation are still not finished. Also it shown that immunosuppression that used as tacrolimus, MMF % mehtylprednisolon can affect viability & proliferation of Treg in dose dependent manner. For this reason several studies are try to find the best time for Treg infusion.
References:
1.Romano M., Fanelli G., Albany C., et al. Past, Present, and Future of Regulatory T cells Therapy in Transplantation and Autoimmunity. Front. Immunol. 2019, 10:43.
2 Arce-Sillas A., Alvarez-Luquin D., Tamayo-Dominguez B., et al. Regulatory T Cells: Molecular Action on Effector Cells in Immune Regulation. Journal of Immunology Research. 2016
3 Corthay A. How do Regulatory T cells Work. Scandinavian Journal of Immunology. 2009, 70: 3260336.
Mahmoud Hamada
3 years ago
Treg cells are a subclass of T cells , they are characterized by expression of FoxP3 transcription factor. Which is the key gene of these cells maturation.
T reg also express CD25, IL2 alpha chain.
These cells are a key player in mitigating autoimmune and alloimmune response via mitigating eosinophilia, IgE and inflammatory mediators.
Professor Ahmed Halawa
Admin
3 years ago
Dear All What is FOXP3 and what its role and relation to Treg?
the forkheadbox transcription factor Foxp3 is newsepcific marker of treg cells was dicover in 2003 and found that its expression very important and necssary due to thier suppressive activity , in animal study on scurfy mice which lack the expresion of FOXP3 would develop sever lymphoprolerative autoimmune disease , and in human studies found mutaion in the FOXP3 gene can lead to autiimmune disorders
It is a transcription factor localized intracellularly and its most reliable marker for Treg cells. It is mostly restricted to CD4 T cells, but some CD8 express it.it essential for T-cell function and its defects lead to fatal immune dysregulation.it is essential for the maintenance of a developmentally established suppressive program in mature Treg in the periphery.
Foxp3 is a specific marker of Treg cells which its expression is necessary for Treg suppressive activity. It was found that mutation of Foxp3 gene in human can cause autoimmune disease.
Foxp3 is a transcription factor, considered to be most reliable marker of Treg cells. It has an important role in function of Treg. Mutation in FoxP3 gene causes lymphoproliferative disorders and autoimmune diseases due to poor suppressor function.
Reference:
Corthay A. How do regulatory T cells work? Scand J Immunol 2009;70:326-336.
FOXp3 (Forkhead/ winged helix transcription factor box P3) is a transcription factor acting as a marker for Treg. Treg can be classified on the basis of FoxP3 :
a) Resting Treg: CD45RA+ FoxP3 high
b) Activated Treg: CD45RA- FoxP3 high
c) Non suppressive Treg: CD45RA- FoxP3 low
Role of FOXP3 in Treg:
FOXP3 is required in signaling mechanisms of Treg leading to increased expression of Tregs. Also, it stabilizes the phenotype of Tregs.
Reference:
Schmidt JV, Han JM, Macdonald KG, et al. The role of FOXP3 in regulating immune responses. Int Rev Immunol 2014;33:110-128.
FOXP3 is a transcription factor that was discovered at 2003 as a specific marker for Tregs and it’s expression is necessary for their immune suppressive function.
What is FOXP3 and what its role and relation to Treg? It is an intracellular transcription molecules which is present in large amount in T reg and is important for the development and function of them.1 it can be found also in CD8+cells. T reg can lose it and eventually lose its suppressant effect2 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, Behdad1,2,4Regulatory 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 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.
Foxp3 is transcription factor express by Treg CD4 lymphocytes so it is marker and way of monitor their activity
Sherif Yusuf
3 years ago
What is Treg and how it is activated?
T regulatory (Treg) cells are a subclass of CD4 T cells that is responsible for suppression of immune response, it constitute 5-10% of CD4 positive T cell population, it is either thymus derived( tTregs) or peripheral derived (pTregs) (1)
Characterized by expression of CD4, CD25 and FOXP3 (CD4+CD25+FoxP3+)
It was found that mutation in FOXP3 locus is associated with Treg dysfunction that lead to severe autoimmunity (2)
Transformation of naive CD4+ T cell to pTreg occur due to repeated stimulation to non- self antigen or exposure to certain cytokines (IL10, TGF-β) (3)
What is the proposed mechanism(s) of induction of tolerance by Treg?
Treg is important in initiating and maintaining peripheral tolerance as they suppress immune response by either contact inhibition through surface expression of CTLA-4 medicated by Foxp 3 or by non contact inhibition through the release of IL10, TGF-β
The net result is superssion CD4 T cell, supression of CD8+ T cells, and may supress B cells and denderitic cells.
How would you implement Treg monitoring in clinical transplantation
1. In a study addressing the relation between graft rejection in liver transplant patients and the Tregs/Th17 ratio which was determined by FCM it was found that Lower ratio was found in recipients with graft rejection.
2. Phase 1 clinical trials demonstrate safety and effectiveness of transfusion of adopted Treg in the treatment of DM1 and in BM, liver and kidney transplantation (4, 5, 6, 7) with superiority of antigen(donor)specific over polyclonal Treg (8)
3. Several studies demonstrated safety and efficacy of manipulation of CD4+ T conv cells to express FOXP3 in hemophilia and type 1 DM, rheumatoid arthritis (9, 10, 11)
4. Transducing Treg with chimeric antigen receptors (CAR)
REFERANCES
1. Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S, et al. Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol. (2013) 14:307–8.
2. Lyon MF, Peters J, Glenister PH, Ball S, Wright E. The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles wiskott-aldrich syndrome. Proc Natl Acad Sci USA. (1990) 87:2433–7.
3. Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H. Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol. (2005) 6:1219–27.
4. Trzonkowski P, Dukat-Mazurek A, Bieniaszewska M, Marek-Trzonkowska N, Dobyszuk A, Juscinska J, et al. Treatment of graft-versus-host disease with naturally occurring T regulatory cells. Biodrugs. (2013) 27:605–14.
5. Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, Grabowska M, Derkowska I, Juscinska J, et al. Therapy of type 1 diabetes with CD4(+)CD25(high)CD127-regulatory T cells prolongs survival of pancreatic islets – results of one year follow-up. Clin Immunol. (2014) 153:23–30.
6. Todo S, Yamashita K, Goto R, Zaitsu M, Nagatsu A, Oura T, et al. A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation. Hepatology. (2016) 64:632–43.
7. Sanchez-Fueyo A, Whitehouse G, Grageda N, Cramp ME, Lim TY, Romano M, et al. Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation. Am J Transplant. (2019) 20:1125–36.
8. Romano M, Fanelli G, Albany CJ, Giganti G, Lombardi G. Past, present, and future of regulatory T cell therapy in transplantation and autoimmunity. Front Immunol. (2019) 10:43.
9. Herzog RW, Kuteyeva V, Saboungi R, Terhorst C, Biswas M. Reprogrammed CD4(+) T cells that express FoxP3(+) control inhibitory antibody formation in hemophilia A mice. Front Immunol. (2019) 10:274
10. Jaeckel E, von Boehmer H, Manns MP. Antigen-specific FoxP3-transduced T-cells can control established type 1 diabetes. Diabetes. (2005) 54:306–10.
11. Beavis PA, Gregory B, Green P, Cribbs AP, Kennedy A, Amjadi P, et al. Resistance to regulatory T cell-mediated suppression in rheumatoid arthritis can be bypassed by ectopic foxp3 expression in pathogenic synovial T cells. Proc Natl Acad Sci USA. (2011) 108:16717–22.
Regulatory T cells are naturally occurring immune modulatory cells, constitute diverse of cells, many Tregs originate from thymus, others arise in periphery from naïve CD4+ T cells on suboptimal exposure to antigens. (1)
The best characterized are CD4+ cells that express high level of IL-2 receptor alpha chain CD25 with transcription factor Foxp3. (2) CD4+ CD25+Foxp3+ natural Tregs play a role in suppression of self reactive cells and are associated with better graft survival. (3)
proposed mechanisms of induction of tolerance:
Treg prevent initiation of unwanted immune activation and suppress ogoing immune response to limit tissue destruction (4)
A study showed that Treg infiltrating the transplanted kidney may have a role in promoting healing by inhibition of inflamatory cytokines produced by other T cells. (5)
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 (6) Metabolic interference:
Treg express high levels of CD25 which depletes IL-2 that is important for survival & function of T cells. (7) Inhibitory cytokine release:
Treg release immune suppressive cytokines (IL-10, IL-35) that prevent T cell proliferation and APC maturation. (8) Cytolysis:
Treg secrete granzymes and perforins which cause apoptosis (9) Targeting APC:
Treg express CTLA-4 which blocks binding of APC to CD28 causing decreased T cell activation. (10)
Recent studies showed that Treg derived exosomes inhibit T cell proliferation in vitro. (11)
Monitoring the effect of Treg:
The aim of using Treg in transplantation is to decrease immunosuppression protocols, It is important to assure effective expansion of Treg, monitor their long term stability, decrease the risk of nonspecific immunosuppression related to cancer. (12)
Number of Treg in kidney transplant patients with solid tumor was higher than patients without tumors. (13) It is important to develop screening program to exclude presence of tumors before starting infusion of Treg. (11)
A study labelled expanded Treg to monitor the transferred cells by flowcytometry (14)
protocol kidney biopsies, monitoring DSA may be necessary (15)
(1) Panduro, M., Benoist, C. & Mathis, D. Tissue Tregs. Annu. Rev. Immunol. 34, 609–633 (2016)
(2) Martin-Moreno, P.L., Tripathi, S. and Chandraker, A., 2018. Regulatory T cells and kidney transplantation. Clinical Journal of the American Society of Nephrology, 13(11), pp.1760-1764.
(3) L. Ma, H. Zhang, K. Hu, G. Lv, Y. Fu, D.A. Ayana, P. Zhao, Y. Jiang, The imbalance between Tregs, Th17 cells and inflammatory cytokines among renal transplant recipients, BMC Immunol. 16 (1) (2015) 56.
(4) TangQ,BluestoneJA.TheFoxp3+regulatoryTcell:Ajackof alltrades,masterofregulation.NatImmunol2008;9:239–244
(5) . GandolfoMT,Jang HR, Bagnasco SM, Ko GJ,Agreda P, Satpute SR, Crow MT, King LS, Rabb H: Foxp31 regulatory T cells participate in repair of ischemic acute kidney injury. Kidney Int 76: 717–729, 2009
(6) 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.
(7) akaguchi S, Sakaguchi N, Asano M, ItohM, Toda M. Immunologic self-tolerancemaintained by activated T cells expressingIL-2 receptor alpha-chains (CD25).Breakdown of a single mechanism of self-tolerance causes various autoimmunediseases. J Immunol 1995; 155: 115.
(8) Sawant D, Hamilton K, Vignali D.Interleukin-35: expanding its job profile.J Interfe ron Cytokine Res 2015; 35: 499.
(9) Vignali D, Collison L, Workman C.How regulatory T cells work. Nat RevImmunol 2008; 8: 523.
(10) Qureshi OS, Zheng Y, Nakamura K,et al. Trans-endocytosis of CD80 andCD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science2011; 332: 600.
(11) Smyth LA, Ratnasothy K, Tsang JY, et al.CD73 expression on extracellular vesiclesderived from CD4+ CD25+ Foxp3+ Tcells contributes to their regulatoryfunction. Eur J Immunol 2013; 43: 2430.
(12) Martin-Moreno, P.L., Tripathi, S. and Chandraker, A., 2018. Regulatory T cells and kidney transplantation. Clinical Journal of the American Society of Nephrology, 13(11), pp.1760-1764.
(13) Hope CM, Grace BS, Pilkington KR et al (2014) The immune
phenotype may relate to cancer development in kidney transplant
recipients. Kidney Int 86:175–183
(14) Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, Herold KC, Lares A, Lee MR, Li K, LiuW, Long SA, Masiello LM, Nguyen V, Putnam AL, Rieck M, Sayre PH, Tang Q: Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med 7: 315ra189, 2015
(15) Chandran S, Tang Q, Sarwal M, Laszik ZG, Putnam AL, Lee K, Leung J, Nguyen V, Sigdel T, Tavares EC, Yang JYC, Hellerstein M, Fitch M, Bluestone JA, Vincenti F: Polyclonal regulatory T cell therapy for control of inflammation in kidney transplants. Am J Transplant 17: 2945–2954, 2017
CD4+ T lymphocytes differentiate into 4 subclasses of T helpers and one regulatory subpopulation (T- reg), while CD8+ differentiate into cytotoxic T cell TCL.
Tregs are a specialized subpopulation of T cells that act to suppress immune response, thereby maintaining homeostasis and self-tolerance. Tregs produced by a normal thymus are called natural, while those formed by differentiation of naive T cells outside the thymus (the periphery) are termed adaptive.
Natural Treg are characterised as expressing both the CD4 T cell co-receptor and CD25, which is a component of the IL-2 receptor. Treg are thus CD4+ CD25+. Expression of the nuclear transcription factor Forkhead box P3 (FoxP3), which is localized intracellulary, is the defining property which determines natural Treg development and function. Additional markers of natural Tregs are CD152 (CTLA-4) and GITR (glucocorticoid-induced TNF receptor). Tregs can be usually identified by flow cytometry.
-Tregs suppress activation, proliferation and cytokine production of CD4+ T cells and CD8+ T cells, NK cells, and Antigen Presenting Cells (APCs), are thought to suppress B cells and T cells and thereby maintain the critical balance between self tolerance and autoimmunity.
-Tregs exert their functions through modulation of APC functions, production of immunoregulatory cytokines such as IL-10, TGF-β, and IL-35, which can contribute to Teff cell suppression. Tregs express coinhibitory receptors like CTLA4 and TIGIT which can also explain their immune inhibitory effect.
Dysregulation in Treg cell frequency or functions may lead to the development of autoimmune disease. Therapeutical Treg modulation is considered to be a promising approach in preventing allograft rejection.
The clinical application of T reg in kidney are related to the objective of achieving tolerance while maintaining tissue repair and managing acute rejection.
A recent study has shown that inducible Treg treatment in a murine model decreased serum donor-specific antibody levels and deposition of IgG within allografts, indicating a potential use in the treatment of humoral rejection.
With regards to the number of Tregs necessary to achieve tolerance, more important than the total dose administered may be increase Tregs to at least 30% of T effectors.
Effect of immunosuppressive drugs on T reg:
-Drugs that alter T reg viability in terms of effect reduction : CNI, MMF, IL2, ATG, B7:CD28 inhibitor
-Drugs that can cause generation/expansion of Treg: mTORi, Alemtezumab, Metformin, Erythropoetin
-Glucocorticoids appear not to affect Tregs
Excellent Mohamed
I can see your effort. Keep going.
saja Mohammed
3 years ago
Normal immune system produces subsets of specialized T cells, called regulatory T cells (Tregs) that are specific for immune suppression. Disruption in the development or function of Tregs is a primary cause of autoimmune, allergic, and inflammatory diseases in humans and animals.
the normal thymus produces functionally mature Tregs; mature Tregs persist in the peripheral lymphoid tissue .Treg deficiency in the periphery can lead to chronic T cell-mediated autoimmunity and immunopathology.
Tregs inhibit or regulate function of other immune cells like can promote the down regulation of dendritic cell CD80 and CD86 by a CTLA-4-dependent mechanism. other specialized Tregs may further differentiate to kill or inactivate responder T cells by secreting granzyme/perforin or cytokines (like IL-10).
Treg cells can be generated either in vivo or ex vivo and open hope for new therapies by induce and maintain tolerance .
Treg cells, subsets of T cells inhibit or regulate function of other immune cells so inhibit immune response to self and non-self antigens so prevent autoimmune diseases. It comes from differentiation of naiive Tcells outside thymus (periphery), and responsible for maintenance of peripheral tolerance, and has anti-tumor function.
Treg are CD4+CD25+, they express nuclear transcription factor FoxP3 which is responsible for its regulatory inhibitory function of Treg and can be used as a marker to monitor Treg post transplant.
Treg cells were activated by :
1- IL-2 lead to its clonal expansion and increased its number.
2- CD28 costimulation will lead to IL-2 secretion which increase Treg numbers.
Mechanism of Treg cells in inducing immune tolerance:
1- Release of inhibitory cytokines like IL-10, TGF-β and IL-35.
2- Treg cells mediate cell lysis by certain mediators like granzyme A and B , and perforin.
3- Apoptosis mediated by cytokine deprived state as Treg cells consume IL-2.
4- Modulate dendritic cell maturation or function; cytotoxic T lymphocyte antigen 4 (CTLA-4) interacts with CD-80/CD-86 and produce inhibitory pro apoptotic molecules.
Tregs are CD4+ cells that express high level of CD25 along with transcription factor FOXP3. the use of these cells in transplantation is to induce immune tolerance, reduction of immunosuppression, maintaining tissue repair & managing rejection.1
These CD4+,CD25+ Tregs constitute 5%- 10% of peripheral T cells.2
In 1995 small proportion of CD4+,CD25+ was described and their relationship to autoimmune disease was identified.3
In 2003 FOXP3 was discovered.
In recent years preclinical studies shows how the transfer of Tregs prevents GVHD & allograft rejection.
In 2009, the first clinical trial for using Tregs was published
Multiple subpopulations of Tregs were distinguished by the expression of different surface markers, mechanism of activation and how they function.
Tregs can be divided into:
I. naive/ resting cells expressing CD45RA+FOXP3low.
II. effector Tregs expressing CD45RA-FOXP3high.
III. cytokine-producing Tregs expressing CD45RA-FOXP3low.3
Tregs enhance healing of the injured kidney tissue during ischemia reperfusion probably by negative modulation of proinflammatory cytokines.
In acute rejection , recipient derived T cells contribute to graft tolerance if they acquire a resting tissue resident phenotype. A study showed that inducible Treg treatment in a murine model decrease DSA level and IgG deposition within the allograft indicating a potential role in the treatment of ABMR.
It can not be assumed that tolerance induced by Tregs is stable, so monitoring is required, some studies suggested to monitor the infused cells with flow cytometry, however, performing protocol biopsies after Tregs infusion to assess changes in inflammation and monitoring DSA may be necessary.1
References:
Martin-Moreno P.L., Tripathi S.,Chandraker A. Regulatory T Cells and Kidney Transplantation.Clin J Am Soc Nephrol. 2018, 13: 1760–1764.
Hu M., Wang Y.M.,Wang Y., Zhang G.Y. Regulatory T cells in kidney disease and transplantation.Kidney International (2016) 90, 502–514.
Romano M., Tung S.L., Smyth L.A., Lombardi G.Tregtherapyintransplantation:ageneraloverview. TransplantInternational2017;30:745–753.
Treg cells are a subset of thymus derived CD4+ T cells expressing high levels of IL-2Rα (CD25). Tregs play a crucial role in maintaining immune homeostasis and preventing autoimmunity. CD25 and (FOXP3) is not sufficient for characterizing human Tregs, since effector T cells can upregulate these markers after activation. However methylation status of (TSDR) , a conserved non-coding element within the FoxP3 gene locus, can be used for the identification of the “real” human Tregs. The thymus is the crucial organ for the generation of Tregs. CD4 single positive (SP) cells , following a TCR signal of high strength undergo negative selection, whereas those receiving TCR signals of intermediate strength are able to escape deletion and are committed to differentiate into Tregs. In addition to tTreg, naïve FOXP3−CD4+ T cells can differentiate in the periphery to become FOXP3+cells, which are known as induced Tregs (iTregs) or peripheral Tregs (pTregs). The generation of iTregs is likely promoted by non-self-antigens (allergens, food, microbiota. . iTregs controls immune responses to commensal antigens and prevent allergic type reactions.
The mechanisms used by Tregs to suppress different immune cells can either be considered direct whereby Tregs themselves elicit a direct response on a target cell, or indirect, in which a third-party cell or molecule is affected and in turn suppresses the target cell .
Direct mechanisms include the secretion of cytokines such as IL-10, TGFβ and IL-35 and the production of granzyme and perforin, enzymes leading to apoptosis in target cells .
Indirect mechanisms include the expression of CD39/CD73, which deplete the microenvironment of extracellular ATP via the generation of adenosine and AMP, molecules with immunosuppressive effects.
T regs thus suppress T cells, B cells, monocytes, dentritic cells, granulocytes and innate immune cells.
clinical studies have shown the safety and feasibility of Tregs infusion in preventing graft rejection. Immunosuppressive drugs like tacrolimus, mycophenolate and methylprednisolone reduced Tregs’ viability and proliferation in a dose dependent manner. Different strategies are now under investigation with the aim to tailor the immunosuppressive regimen to the Tregs or find the best timing for their infusion. Treg localization and migration is the the main challenge.
Ongoing clinical trials will be crucial to better understand the tolerated Treg dose, timing of infusion and the immunosuppressive regimen to preserve/favor them. Best strategy is represented by the combined therapy whereby antigen-specific Treg will be infused together with either low dose of IL2, rapamycin or in the future TNFR2 agonists.
Thank you for mentioning the effects of Tregs in IRI, acute rejection. Absolutely right, the tolerance induced by Tregs is stable, and this is one of the limitations of the studies using them.
Thankyou Hoda now you mentioned roles played by Tregs in
IRI
Acute rejection
ABMR
could there be a role in chronic rejection
And is there a relation between degree of HLA mismatch and role of Tregs.
The role of T-cell in transplantation ;
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;
1-thymus derived Tregs (natural).
2- 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?
1-Calcinurin inhibitors decrease T-reg viability and proliferation.
2-The effects of mycophenolic acid on T-reg appear to be more variable .
3-Glucocorticoids appear not to affect T-regs.
4-mTOR inhibitors promote differentiation and expansion of T-reg as well as increase Foxp3expression,although their effect may decline over time .
5-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.
6-There are none immunosuppressive drugs have been shown to increase T-reg population; Metformin and Erythropoietin
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Kim KW, Chung BH, Kim BM, Cho ML, Yang CW: The effect of mammalian target of rapamycin 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
Gurkan S, Luan Y, Dhillon N, Allam SR, Montague T, Bromberg JS, Ames S, Lerner S, EbciogluZ,NairV,DinavahiR, Sehgal V,Heeger P, SchroppelB,MurphyB: Immunereconstitution followingrabbit antithymocyte globulin. Am J Transplant 10: 2132–2141, 2010
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
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What is Treg and how it is activated?
What is the proposed mechanism(s) of induction of tolerance by Treg?
How would you implement Treg monitoring in clinical transplantation
Tregs can be monitored in clinical transplantation by the specific markers related to Treg including FOXP3, CD25, CTLA4, GITR and CD127. (3) These markers are T cell activation markers, hence they are not specific for Treg.
Tregs have been used in clinical trials in transplantation as a way to induce tolerance. Deuterium labelled pTregs have been used in kidney transplant recipients. (4) Post transfusion, these could be tracked by their deuterium signals. Similarly, Indium labelled T regs have also been transfused in kidney transplant recipients and monitored using SPECT.
REFERANCES
1) Corthay A. How do regulatory T cell work? Scand J Immunol 2009;70:326-336.
2) Chandran S, Tang Q, Sarwal M, et al. Polyclonal regulatory T cell therapy for control of inflammation in kidney transplants. Am J Transplant 2017;17:2945-2954.
3) Hutchinson JA, Riquelme P, Sawitzki B, et al. Cutting Edge: Immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients. J Immunol 2011;187:2072-207
4) Herzog RW, Kuteyeva V, Saboungi R, Terhorst C, Biswas M. Reprogrammed CD4(+) T cells that express FoxP3(+) control inhibitory antibody formation in hemophilia A mice. Front Immunol. (2019) 10:274
5). Jaeckel E, von Boehmer H, Manns MP. Antigen-specific FoxP3-transduced T-cells can control established type 1 diabetes. Diabetes. (2005) 54:306–10.
6). Beavis PA, Gregory B, Green P, Cribbs AP, Kennedy A, Amjadi P, et al. Resistance to regulatory T cell-mediated suppression in rheumatoid arthritis can be bypassed by ectopic foxp3 expression in pathogenic synovial T cells. Proc Natl Acad Sci USA. (2011) 108:16717–22.
T reg have important role in immune homeostasis and balance of immune response. They are of 2 main types:
. Thymus -derived CD4+CD25+Foxp3,nTreg
.Adaptive /induced T reg from peripheral naiive cells
Foxp3 is the major transcription factor which influences behavior and function of T reg cells. T reg produce cytokines like TGFB,IL-10,and IL-35.Th3 cells produce TGBF and Tr1 secrete IL-10.
MMF and rapamycin expand iT reg. CNI inhibit T reg function through targeting IL-2 production. Tac inhibits IL-2 production .Post Tx effect of immunosuppressive agents on T reg must be put in consideration .
References:
Bryan ,E et alT reg induction ,migration ,and function in transplantation,J immunol,2012,Nov 15;189(10):4705-4711
Regulatory T cell is a type of CD4+ T cells that elicit regulatory or immunosuppressive actions. They provide immune tolerance against self-antigens.
Treg activation is antigen dependent process.
Various mechanisms of action of Treg including:
*Contact dependent suppression
*Contact-independent suppression through anti-inflammatory cytokine production.
*Inducing apoptosis through Granzyme/perforin pathways.
Tregs can be monitored by the specific markers related to Treg including FOXP3, CD25, CTLA4, GITR and CD127. These markers are T cell activation markers.
Tregs have been used in trials in Tx aiming for tolerance induction.
Regulatory T cells in the peripheral circulation are characterised as CD4+ with high levels of IL‐2 receptor alpha chain (CD25high) and low levels of CD127 and intracellularly, expressing the forkhead box P3 transcription factor (FOXP3+).However, the adoption of novel deeper immunophenotyping technologies has identified this phenotype to be more heterogeneous than initially considered.These data differ depending on the species, type of Treg cells, differentiation state and microenvironment.Hence, a comprehensive understanding of Treg cell heterogeneity is needed to safely and effectively exploit their therapeutic potential. As such, we consider it timely in this review to outline established and novel data regarding Treg heterogeneity and discuss future lines of inquiry.
In solid organ and bone marrow transplantation (SOT and BMT, respectively), Treg cells have been identified as modulators of both T‐cell‐mediated and antibody‐mediated rejection.However, our understanding of the underlying mechanisms is complicated as effector T cells (Teffs) can adopt the Treg‐like phenotype and functions. In reverse, Treg cells can alter their phenotype and functions to adopt a Th17‐like effector cell profile too. It is important to understand these alterations as they can impact the regulatory balance in the graft.A further limitation is that much of our understanding to date originates from in vitro experiments and in vivo murine (or non‐human primate; NHP or swine) models.It is only in recent years through clinical trials can the in vivo relevance of these mechanisms to humans undergoing SOT be deciphered. These trials mainly involve ex vivo expansion of autologous Treg cells under Good Manufacturing Practice (GMP) conditions utilising various pharmacological agents that promote their differentiation, expansion, stability and function.Considering this recent progress, we consider it timely to outline the recent clinical trials in SOT with a focus on safety.
References
1. Christians U, Klawitter J, Klawitter J et al Biomarkers of immunosuppressant organ toxicity after transplantation: status, concepts and misconceptions. Expert Opin Drug Metab Toxicol. 2011; 7: 175–200.
2. Bahmani B, Uehara M, Jiang L et al Targeted delivery of immune therapeutics to lymph nodes prolongs cardiac allograft survival. J Clin Invest 2018; 128: 4770–4786.
3. Graca L, Cobbold SP, Waldmann H. Identification of regulatory T cells in tolerated allografts. J Exp Med 2002; 195: 1641–1646. [PMC free article] [PubMed] [Google Scholar]
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What is the proposed mechanism(s) of induction of tolerance by Treg?
Defining the mechanisms of Treg-cell function is clearly of crucial importance. Not only would this provide insight into the control processes of peripheral tolerance but it would probably provide a number of potentially important therapeutic targets. Although this quest has been ongoing since interest in Treg cells was reignited in 1995, there has been significant progress in the last few years. From a functional perspective, the various potential suppression mechanisms of Treg cells can be grouped into four basic ‘modes of action’: suppression by inhibitory cytokines, suppression by cytolysis, suppression by metabolic disruption, and suppression by modulation of dendritic-cell (DC) maturation or function.
Inhibitory cytokines, such as interleukin-10 (IL-10) and TGFβ, have been the focus of considerable attention as a mechanism of Treg-cell-mediated suppression. There has also been significant interest in their ability to generate induced (also known as adaptive) Treg-cell populations, either naturally in vivo or experimentally as a potential therapeutic modality. Although the general importance of IL-10 and TGFβ as suppressive mediators is undisputed, their contribution to the function of thymus-derived, natural Treg cells is still a matter of debate.This is partly due to the general perception that Treg cells function in a contact-dependent manner. Indeed, in vitro studies using neutralizing antibodies or T cells that are unable to produce or respond to IL-10 and TGFβ suggested that these cytokines may not be essential for Treg-cell function. However, this contrasts with data from in vivo studies.
* Suppression by inhibitory cytokines:
~ Inhibitory cytokines, such as interleukin-10 (IL-10) and TGFβ, have been the focus of considerable attention as a mechanism of Treg-cell-mediated suppression. There has also been significant interest in their ability to generate induced (also known as adaptive) Treg-cell populations, either naturally in vivo or experimentally as a potential therapeutic modality.
* Suppression by cytolysis:
~ Cytolysis mediated through secretion of granzymes had long been considered the forte of natural killer (NK) cells and cytotoxic CD8+ T lymphocytes (CTLs).
*Suppression by metabolic disruption:
~Several intriguing suppressive mechanisms have been described that could collectively be referred to as mechanisms that mediate ‘metabolic disruption’ of the effector T-cell target. A long-standing debate in the Treg-cell field is whether the high expression of CD25 empowers Treg cells to ‘consume’ local IL-2 and therefore starve actively dividing effector T cells by depleting the
IL-2 they need to survive.
*Suppression by targeting dendritic cells:
~In addition to directly affecting effector T-cell function, Treg cells might modulate the maturation and/or function of dendritic cells (DCs) required for effector T-cell activation. This has long been considered an attractive idea but there has been only limited data in support80. However, intravital microscopy has revealed direct interactions between Treg cells and DCs in vivo, which was proposed to attenuate effector T-cell
activation by DCs.
References:
1. Sakaguchi S, et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol. Rev. 2001;182:18–32.
2. Shevach EM, et al. The lifestyle of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells. Immunol. Rev. 2006;212:60–73.
3. Xystrakis E, Boswell SE, Hawrylowicz CM. T regulatory cells and the control of allergic disease. Expert. Opin. Biol. Ther. 2006;6:121–133.
4. Coombes JL, Robinson NJ, Maloy KJ, Uhlig HH, Powrie F. Regulatory T cells and intestinal homeostasis. Immunol. Rev. 2005;204:184–194.
5. Belkaid Y. Regulatory T cells and infection: a dangerous necessity. Nat Rev. Immunol. 2007;7:875–888.
What is Treg and how it is activated?
T regulatory (Treg) cells are a T lymphocyte subpopulation that control the balance between immune activation and tolerance. Treg cells can originate from two main sources: thymus-generated natural Tregs (tTreg) and peripheral inducible Tregs (pTreg), generated during immune priming. Several factors are required for tTreg generation; these cells are strongly dependent on TCR and CD28 signals and on several cytokines. Cytokines contribute to Treg maintaining via 𝛾 chain signaling of IL-2 and IL-15, and TGF𝛽 increases FOXP3 expression.However, certain cytokines like as TNF-𝛼 have a controversial role in tTreg generation.
On the other hand, pTreg generation requires stimulation in an anti-inflammatory milieu, a process where dendritic cells are critically involved. According to cytokine production, Tregs have been further classified; for instance, Th3 cells are characterized by TGF𝛽 production; Tr1 cells produce IL-10, and Tr35 cells produce IL-35. The suppressive capacity of these sub- sets is contact-independent. While the expression of the transcription factor FOXP3 can be transient in humans, this factor is associated with a suppressive function in mice. Thus, mouse Treg cells show the classical phenotype CD3+CD4+CD25+FOXP3+ .
***Molecular Mechanisms of Treg-Mediated Suppression:
~Several action mechanisms by which Treg cells control the immune response have been reported:
(1) inhibition by immunoregulatory cytokines such as TGF𝛽, IL-10, and IL- 35.
(2) inhibition by cytolysis of effector cell by producing granzyme and perforin.
(3) metabolic interruption, including an inhibition of the proliferative response via IL-2 receptor, cAMP-mediated metabolic inhibition, and immunomodu- lation mediated by the A2 adenosine receptor.
(4) inter- action with dendritic cells that modulates their function and maturation.
***References:
1-A. Schmidt, N. Oberle, and P. H. Krammer, “Molecular mechanisms of treg-mediated T cell suppression,” Frontiers in Immunology, vol. 3, article 51, 2012.
[2]A.L.Perdigoto,L.Chatenoud,J.A.Bluestone,andK.C.Herold, “Inducing and administering tregs to treat human disease,” Frontiers in Immunology, vol. 6, article 654, 2016.
[3] D. A. A. Vignali, L. W. Collison, and C. J. Workman, “How regulatory T cells work,” Nature Reviews Immunology, vol. 8, no. 7, pp. 523–532, 2008.
[4] M. Dhainaut and M. Moser, “Mechanisms of surveillance of dendritic cells by regulatory T lymphocytes,” Progress in Molecular Biology and Translational Science, vol. 136, pp. 131– 154, 2015.
[5] M. Saraiva and A. O’Garra, “The regulation of IL-10 production by immune cells,” Nature Reviews Immunology, vol. 10, no. 3, pp. 170–181, 2010.
●Definition of t. Reg how it is activated ?
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.[2] 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.
The following represent some of the proposed mechanisms of immune suppression:
. Regulatory T cells produce a number of inhibitory cytokines. These include TGF-β,Interleukin 35,and Interleukin 10. It also appears that regulatory T cells can induce other cell types to express interleukin-10.Regulatory T cells can produce Granzyme B, which in turn can induce apoptosis of effector cells. Regulatory T cells from Granzyme B deficient mice are reported to be less effective suppressors of the activation of effector T cells.Reverse signalling through direct interaction with dendritic cells and the induction of immunosuppressive indoleamine 2,3-dioxygenase.Signalling through the ectoenzymes CD39 and CD73 with the production of immunosuppressive adenosine.Through direct interactions with dendritic cells.
●mechanism of tolerance induction by t reg cells?
potential suppression mechanisms of Treg cells can be grouped into four basic ‘modes of action’: suppression by inhibitory cytokines, suppression by cytolysis, suppression by metabolic disruption, and suppression by modulation of dendritic-cell (DC) maturation or function .
Reference
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2665249/#!po=11.7424
Tregs:
were initially characterized as CD4 CD25 T cell .
Tregs constitute 5% to 10% of peripheral CD4 T cells in Normal healthy humans and
have a major role in immune homeostasis and in suppressing unwanted inflammatory.
Responses to self-antigens.Foxp3 was identified as the key transcription factor that
characterizes this lineage of Thymically derived Tregs.(1)
In addition to CD4þFoxp3þ Tregs, there other T-cell Subsets with suppressive activity.
These include CD4þ type 1Treg that secrete interleukin (IL)-10, 21 transforming growth
Factor-b (TGF-b) Tregs (TH3 cells), regulatory natural killer T Cells, regulatory T cells,22
and double-negative Tregs andCD8þ Tregs.17.
Functional characteristics:
The suppressive function:
of Tregs includes direct cell contact and regulatory cytokines such as TGF-b and IL-10.
Tissue-repair capacity of Tregs:
Tregs, in addition to reduce inflammation and supporting tissue repair.
Alternative Tregs subsets:
Tregs have been shown to effectively reduce renal injury in animal models of kidney
disease and injury.
The role of Tregs in tolerant kidney transplant:
Foxp3 Tregs have been shown to play important Role in the induction and maintenance
of renal allograft tolerance in various animal transplant models.
One of most valuable models is donor-specific tolerance of renal allografts.
Blocking costimulatory pathways:
Can induce allograft tolerance in major histocompatibility complex (MHC) mismatched
kidney transplant.(2)
Recent data suggest that Foxp3þ Tregs both limit graft-versus-host disease and maintain
mixed chimerism, assisting in tolerance development in mixed- and full-chimerism
models of kidney allograft tolerance and that their numbers are potentially
increased in the transplanted organ.
High levels of FOXP3⁺ Tregs, specifically CXCR3⁺ Tregs and HLA-DR high⁺ CD45RA_
Tregs in peripheral blood that produce high levels of interferon-g, are associated with
renal allograft survival and function. TGF-b and IL-10 have both been identified as being
associated with long-term renal allograft acceptance. Induced Tregs secreting
interferon-g demonstrate suppressive function in vitro and are associated with renal
allograft acceptance in kidney transplant patients.
Treg therapy in kidney disease and transplantation.
Anti-CD3 and CD28 antibodies, with IL-2and/or rapamycin, these have been shown to be
potent and therapeutic in limiting rejection.
Reference:
1- Min Hu. Yuan Min Wang.Yiping Wang et al. Regulatory T cells in kidney disease
and transplantation. Kidney International (2016) 90, 502–514.
2-1- Min Hu. Yuan Min Wang.Yiping Wang et al. Regulatory T cells in kidney disease
and transplantation. Kidney International (2016) 90, 502–514.
1- What is Treg and how it is activated?
2- What is the proposed mechanism(s) of induction of tolerance by Treg?
3- How would you implement Treg monitoring in clinical transplantation?
Regulatory T cell
• T cell which regulate and suppress immune system
• Produced by normal thymus called natural
• Formed by differentiate of naïve T cell outside the thymus ( the peripheral or in cell culture called adaptive)
• Treg are CD4+ Cd 25+ due to expressing both CD 4 T cell co receptor and CD 25
• Forkhead box P3 ( FoxP3) which determines natural Treg development and fucntion
Role of T reg
• Suppress activation, proliferation and cytokine production of CD4+ T cell and CD 8+ T cell
• Thought to suppress B cell and dendritic cells
• Produce soluble messengers which have a suppressive function such as TGF-beta, IL-10 and adenosine
• Markers of natural Treg – CD152(CTLA-4) and GITR( glucocorticoid induced TNF receptor)
Different types of T cells with regulatory activity:
1. CD4+ Tcells
2. CD8+ T cells
3. Double negative T cells
4. Natural killer (NK) T cell
Treg cell heterogeneity
• Natural T cell (nTreg) / tTreg – grow in the thymus
• pTreg – develop at the perphery by specific stimuli of conventional CD4+ T cell
• iTreg-T cell induced in vitro
Proposed mechanism(s) of induction of tolerance to donor antigens
1. Deletion to donor reactive cells centrally in the thymus and in the peripheral
2. T cell ignorance, or a state of T cell unresponsiveness that is relevant to graft placed at “ immunologically privileged” sites such as the cornea or brain
3. Exhaustion – which the ability of donor -reactive cells to harm the allograft is eliminated as a result of over stimulation and cell death
4. Anergy – state of unresponsiveness that is refractory to further stimulation despite the continuing presence of antigen after transplantation
5. Immunoregulation – an active process whereby the immune response to an allograft is controlled by populations of regulatory immune cells
Treg suppressive mechanisms
• Tregs are able to suppress different cell types by direct and indirect mechanisms
• Direct mechanisms – secretion of cytokines such as IL-10, TGFβ and IL-35 and the production of granzyme and perforin, enzymes leading to apoptosis in target cells
• Indirect mechanisms –expression of CD39/CD73, which deplete the microenvironment of extracellular ATP via the generation of adenosine and AMP, molecules with immunosuppressive effects
• They can sequester, by the high expression of CD25, IL-2 from the microenvironment reducing effector T cells proliferation
• IL-2 starvation reduces NKs from proliferating and exhibiting effector functions
• NKs can be directly affected by Tregs in a membrane bound TGF-ß dependent manner
• Tregs have been observed to have a direct effect on B-cells via PDL1/PD-1 interaction and DCs via both CTLA-4 and LAG-3. CTLA-4 blocks co-stimulation reducing CD80/CD86 expression and it induces upregulation of Indoleamine 2,3-dioxygenase
• The expression of CD39 on Tregs mediate the conversion to ATP to adenosine and AMP and reduce T effector proliferation
• Tregs can also skew monocyte toward M2 macrophages and prevent their differentiation in pro-inflammatory M1 macrophages. They can similarly induce a suppressive phenotype in neutrophils and reduce ILC2 cytokine secretion
The TRACT trial -Immunophenotypic analysis of the subjects shows a significant (9- to 20-fold) increase in the percentage of circulating CD4+CD127–CD25hiFoxp3+ cells in peripheral blood. The authors concluded that the safety of the phase I trial allows planning for a phase II trial; however, because the Tregs were infused following severe T cell depletion, the percentage increase in Tregs may not be meaningful or clinically relevant if the absolute number of Tregs is very low.
TASKp trial- showed that Treg infusions were safe and were not associated with acute side effects, nor did infusion precipitate episodes of acute rejection. Kidney biopsies performed 2 weeks after the infusion showed a marked decrease in inflammation in two of three patients that was associated with a concomitant decrease in inflammatory gene expression. The deuterium label used to track the infused Tregs was found exclusively in the Treg population. The results of this pilot study suggest that maintenance immunosuppression did not negatively impact Treg pharmacokinetics or lineage stability.
The TASK trial-Renal allograft inflammation below the threshold of rejection is a unique setting for testing the therapeutic effect of Tregs. Routine protocol kidney biopsies in patients with stable renal function show that 10%–20% have inflammatory mononuclear cell infiltration in the renal graft. There is no consensus about what remedial therapy, if any, to use for subclinical inflammation
implement Treg monitoring in clinical transplantation
Few questions to be answered before implementations
1. What is the optimum dosage of Tregs?
2. Are alloantigen-reactive Tregs required for efficacy as compared with polyclonal Tregs, how about the price of manufacturing vs benefit?
3. A single Treg infusion enough to induce tolerance, thereby extending the biological effects of Tregs indefinitely, or require frequent dosing to replenish Tregs?
4. What are the specific requirements, particularly for adjunct immunosuppressants, to maximize the survival and function of infused Tregs?
I would like to use Tregs have been proven in clinical trials in transplantation to induce tolerance. Deuterium labelled pTregs have been used in kidney transplant recipients. Post transfusion, these could be monitored by their deuterium signals. Indium labelled T regs have also been transfused in kidney transplant recipients and monitored using SPECT. Probably for now, these metjodas can be used while searching for more evidences role of Treg in monitoring post tranplantation.
References
Muhammad Atif, Filomena Conti.Regulatory T cells in solid organ transplantation.
Clin Transl Immunology. 2020; 9(2): e01099.
Hu, M., Rogers, N. M., Li, J., Zhang, G. Y., Wang, Y. M., Shaw, K., O’Connell, P. J., & Alexander, S. I. (2021). Antigen Specific Regulatory T Cells in Kidney Transplantation and Other Tolerance Settings. In Frontiers in Immunology (Vol. 12).
Malhotra, Deepali; Linehan, Jonathan L. Tolerance is established in polyclonal CD4+ T cells by distinct mechanisms according to self-peptide expression patterns. Nature Immunology.2016: 17 (2): 187–195.
Kidney transplantation: Principles and Practice by Stuart J Knechtile
Handbook of kidney transplantation by Gabriel M. Danovitch
T regs are a subgroup of T cells that have immunoregulatory effects. 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.
· Tregs or regulatory Tcells are important to induce tolerance by expression of CD25 or secretion of IL-10 and TGF β.
· IFN- γ can induce T regs and inhibit Th 17 cells.
1. Issa F, Schiopu A, Wood KJ. Role of T cells in graft rejection and transplantation tolerance. Expert Rev Clin Immunol. 2010 Jan;6(1):155-69.
2. Hu, M., Rogers, N. M., Li, J., Zhang, G. Y., Wang, Y. M., Shaw, K., O’Connell, P. J., & Alexander, S. I. (2021). Antigen Specific Regulatory T Cells in Kidney Transplantation and Other Tolerance Settings. In Frontiers in Immunology (Vol. 12). https://doi.org/10.3389/fimmu.2021.717594
Treg
are important in maintaining immune homeostasis and in regulating a variety of immune responses, making them attractive targets for modulating immune-related diseases.
There are two main types of Treg: thymus-derived CD4+CD25+Foxp3+ natural Treg (nTreg), and adaptive/induced Treg (iTreg) that develop from naïve T cells in the periphery under tolerogenic conditions .
It has long been established that Fork-head box P3 (Foxp3) is the major transcription factor (TF) that determines the fate, identity, and function of Treg, and Treg regulate immune functions by producing cytokines such as TGFβ, IL-10, and IL-35 (3, 4). However, there are subsets of Treg that do not express Foxp3. For example, TGFβ-producing Th3 and IL-10-secreting Tr1 regulatory T cells also can be potent suppressors in some experimental systems.
Common immunosuppressants used post-transplantation in humans have opposing effects on Treg induction. Both mycophenolate mofetil, an inosine 5’-monophosphate dehydrogenase inhibitor, and rapamycin, the eponymous inhibitor of the mammalian target of rapamycin (mTOR), expand iTreg in vitro and in vivo .In humans, rapamycin (sirolimus) given following treatment with a lympho-depleting anti-CD52 mAb favors Treg expansion
calcineurin inhibitors may prevent Treg induction .Cyclosporine A inhibits Treg function and proliferation .likely by inhibiting IL-2 production .This inhibition of Treg function and proliferation allows for effector T cell proliferation and prevention of peripheral repopulation of Treg following anti-CD52 mAb treatment
FK506 (tacrolimus) also inhibits the transmission of TCR signaling, thus inhibiting IL-2 production. Reports regarding the impact of FK506 on Treg induction vary; it has been reported to inhibit, not affect, or favor Treg induction, likely in a dose-dependent fashion .Thus, post-transplantation immunosuppressive regimens should be chosen with care in order to promote the generation and function of protective Treg and suppress anti-graft immune responses.
Bryna E. Nakayama Y,Treg induction, migration, and function in transplantation. J Immunol. 2012 November 15; 189(10): 4705–4711. doi:10.4049/jimmunol.1202027.
Exellant Dalia well understood controvertial relation of IS and Tregs.
References ;
Eergton M, Scollay R, Shortman (1990) kinetics of mature T- cell development in the thymus. Proc Natl Acad Sci 87: 2579-82
Russel DM, Dembic Z, Morahan G (1991) peripheral deletion of self-reactive B cells. Nature 354: 308-311
Jiang H, Wu Y, Liang B, Zheng Z, Tang G, et al.(2017) An affinity avidity model of peripheral T cell regulation. Journal of clinical investigation 115: 302 -312.
Thankyou but you should elaborate the specific role of each type.
Thnx Prof ;
Thymus derived Treg is the main mediator of central immune tolerance, while peripherally derived T reg regulate peripheral immune tolerance
What is Treg?
Tregs are CD4+CD25high T lymphocytes expressing FoxP3 transcription factor
According to origin Tregs originate in 2 sites,(1) the thymus (tTreg) during the course of positive and negative selection ,(2) peripherally [pTreg) which originate from nonregulatory Foxp3− CD4 T cells (Tconv) after exposure to antigenic stimulation and transforming growth factor-β signaling)
three Treg subsets have been described. central Treg (cTreg), effector Treg (eTreg), and memory Treg (mTreg)
Tregs play a central role in maintaining immune homeostasis, promoting and maintenance of allograft tolerance (1) Prevention of chronic rejection and participate in tissue repair.
differentiation from cTregs to eTregs is critical for the maintenance of immune homeostasis and self-tolerance (2).
mTregs are considered to be a subset of Tregs in nonlymphoid tissues, of a low proliferative state in absence of their cognate antigen Upon re-exposure to cognate antigen, mTregs expand and provide protection against excessive damage (3).
how it is activated?
Treg subsets are activated Upon T cell receptor (TCR) ligation and co-stimulation during antigen presentation by self-MHC class II on recipient APCs.
cTregs that are accumulated in lymphoid organs differentiate into eTregs (4) That then infiltrate both lymphoid and nonlymphoid organs
What is the proposed mechanism(s) of induction of tolerance by Treg?
(1) expression of transcription factors typical of effector cells toward Th1, Th2, or Th17.
· expression of T-bet+TIGIT towards Th-1
· transcription factor IRF-4 towards Th-2
· expression of the Th17-typical factor STAT3 to the regulation of the Th17-mediated immune response and enables the expression of IL-10, Ebi3, granzyme-B, and perforin-1 genes (5)
(2) Antigen-specific suppression caused by the direct Treg–DC (dendritic cell) interaction enabled by the recognition of the specific antigen (Ag) the DC presents as part of MHC-II ,evntually ends in disruption of Ag presentation, cause T effector anergy, or trigger Ag-specific pTreg induction.
(3) Antigen-non-specific mechanisms include:
· enzymes CD39/CD73 on the Treg surface, which cause ATP to degrade to adenosine. Increased adenosine concentration in the microenvironment inhibits DC presentation of antigens and suppresses the proliferation of activated T effectors (6).
· non-specific suppression factors: Treg production of cytokines: TGF-β, IL-10, and IL-35.
They can suppress the activation and proliferation of effector T and B lymphocytes; inhibit antigenic presentation to dendritic cells, which in their turn enable pTreg induction
(4) Ccontact suppression mechanism:
· Treg disrupt the Ca2+ supply to effector lymphocytes, thus disabling the Ca2+-dependent transcription factors NFAT and NF-kB T effectors need in early TCR-dependent activation.
· Perforin-granzyme cytolysis against a CD4+, and CD8+ effector T cells.
(5) Tumor necrosis factors . As Tregs are activated, they acquire TRAIL (TNF-related apoptosis-inducing ligand) expression, while the CD4+ effector cells begin expressing the ligand of this molecule, DR5 (death receptor 5); TRAIL/DR5 interaction induces the apoptosis in effector lymphocytes
(6) Treg lymphocytes simultaneously express the molecule PD-1 and its ligand PD-L1. DC PD-L1 and Treg PD-1 interaction generates a tolerogenic dendritic cell. Treg PD-L1 interacts with PD-1 on the activated effector cells and causes its anergy).
(7) Because of high IL-2R (CD25) expression, Tregs can reduce IL-2 concentrations in the microenvironment, which will negatively affect the proliferative response of CD8+ cells.
How would you implement Treg monitoring in clinical transplantation?
Through Molecular markers, although they are not truly Treg-specific as also can be found in activated conventional Th cells.
· CD25
· cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)
· glucocorticoid-induced tumour necrosis factor receptor family-related gene (GITR)
· lymphocyte activation gene-3 (LAG-3)
· CD127
· forkhead/winged-helix transcription factor box P3 (Foxp3)
Effect of immunesuppression on T reg population:
Negatively affecting Tregs
· Calcineurin inhibitors
o ◦Cyclosporine A
o ◦Tacrolimus (FK506)
Inhibit calcineurin and NFAT activation, which destabilizes Foxp3 expression in Tregs
· Belatacept (CTLA-Ig)
Blocks signaling through co-stimulatory molecule CD28, which is essential for Treg ontogeny and function
· Basiliximab (anti-IL-2R)
Blocks IL-2 receptor signaling
Positively affecting Tregs
· mTOR inhibitors
o ◦Rapamycin
o ◦Everolimus
Inhibit mTORc1 activity. Tregs appear to be less sensitive to mTORc1 inhibition than Tconv
· HDAC inhibitor
o ◦Vorinostat
Inhibits histone deacetylases and promotes gene expression
· Low-dose IL-2
Promotes IL-2R signaling on Tregs. Tregs are more sensitive to low-dose IL-2R signaling than Tconv
· Rabbit anti-thymocyte globulin (rATG)
Depletes both Tconv and Tregs, but Tregs numbers recover faster than Tconv
No or unknown effects on Tregs
· Complement inhibitors
o ◦Eculizumab
Prevent C5 cleavage. No effect on Treg numbers, but function was not assessed83
· Steroids
o ◦Prednisone
o ◦Methylprednisolone
Inhibit pro-inflammatory cytokines. No effects on Tregs in transplant patients92
· Antiproliferative agents
o ◦Mycophenolate mofetil (MMF)
o ◦Azathioprine
Inhibit purine synthesis. Unknown effects on Tregs
Ref:
(1) Tang Q, Bluestone JA. The Foxp3 + regulatory T cell: a jack of all trades, master of regulation. Nat Immun. 2008;9:239–44. [PMC free article] [PubMed] [Google Scholar]
(2) Nagy ZA. Evolutionary origin of the immune system: a dialogue with Rod Langman. Scand J Immunol. 2008;67:313–21. [PubMed] [Google Scholar]
(3) Wang R, Song L, Han G, et al. Mechanisms of regulatory T-cell induction by antigen-IgG-transduced splenocytes. Scand J Immunol. 2007;66:515–22. [PubMed] [Google Scholar]
(4) Cohn M. A rationalized set of default postulates that permit a coherent description of the immune system amenable to computer modeling. Scand J Immunol. 2008;68:371–80. [PMC free article] [PubMed] [Google Scholar]
(5) Chaudhry A, Rudra D, Treuting P, Samstein RM, Liang Y, Kas A, et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science. (2009) 326:986–91. doi: 10.1126/science.1172702
PubMed Abstract | CrossRef Full Text | Google Scholar
(6) Ernst PB, Garrison JC, Thompson LF. Much ado about adenosine: adenosine synthesis and function in regulatory T cell biology. J Immunol. (2010) 185:1993–8. doi: 10.4049/jimmunol.1000108
PubMed Abstract | CrossRef Full Text | Google Scholar
Thankyou Nadia your comments about IS and Tregs is very clear.
Regulatory T cells (Tregs) are a specialized subpopulation of T cells that act to suppress immune response, maintain tolerance to self antigens and prevent autoimmune diseases thereby maintaining homeostasis . It has been shown that Tregs are able to inhibit T cell proliferation and cytokine production and play a critical role in preventing autoimmunity.
Treg cells express the biomarkers CD4 ,FOXP3 and CD25and are thought to be derived from the same lineage as naïve CD4+cells.
Different subsets with various functions of Treg cells exist. Tregs can be usually identified by flow cytometry. The most specific marker for these cells is FoxP3, which is localized intracellulary. Selected surface markers such as CD25high (high molecular density) and CD127low (low molecular density) could serve as surrogate markers to detect Tregs in a routine clinical practice. Dysregulation in Treg cell frequency or functions may lead to the development of autoimmune disease. Therapeutical Treg modulation is considered to be a promising therapeutical approach to treat some selected disorders, such as allergies, and to prevent allograft rejection.
Treg cells can originate from two main sources: thymus-generated natural Tregs (tTreg) and peripheral inducible Tregs (pTreg), generated during immune priming.
Several factors are required for tTreg generation; these cells are strongly dependent on TCR and CD28 signals and on several cytokines. Cytokines contribute to Treg maintaining via γ chain signaling of IL-2 and IL-15, and TGFβ increases FOXP3 expression .However, certain cytokines like as TNF-α have a controversial role in tTreg generation .
On the other hand, pTreg generation requires stimulation in an anti-inflammatory milieu, a process where dendritic cells are critically involved .
According to cytokine production, Tregs have been further classified; for instance, Th3 cells are characterized by TGFβ production; Tr1 cells produce IL-10, and Tr35 cells produce IL-35. The suppressive capacity of these subsets is contact-independent. While the expression of the transcription factor FOXP3 can be transient in humans, this factor is associated with a suppressive function in mice.
Reference:
Regulatory T cells (TREG) and their roles in immune system with respect to immunopathological disorders
Katerina Kondĕlková et al. Acta Medica (Hradec Kralove). 2010.
Regulatory T Cells: Molecular Actions on Effector Cells in Immune Regulation
Asiel Arce-Sillas,1 Diana Denisse Álvarez-Luquín,1 Beatriz Tamaya-Domínguez,1 Sandra Gomez-Fuentes,
What is Treg and how it is activated?
It’s subclass of both Cd4Tcell and cd8tcell but mainly Cd4Tcell
After Naïve tcell exposure to nonself antigens presented on APC and the 3signal activation take place.. secretion of cytokines occurs
Th17 and treg share the same pathway
Cytokines like IL6 and mtor signal favor Th17 pathway but IL2 and TGF beta favor treg pathway.
What is the proposed mechanism(s) of induction of tolerance by Treg?
Contact dependent treg express cd28 on its surface and interact with cd28 on conventional tcell preventing signal 2
None contact dependent by secretion of IL10 and TGF beta which influence inhibitory effect on adaptive immunity
How would you implement Treg monitoring in clinical transplantation?
There’s is multiple markers on treg but foxp3 is the most reliable one
Is transcription factor which important for treg expression and maintain treg phenotyping and its mutation associated with autoimmune diseases
According to markers(foxp3,Cd45Ra) expressed by treg its divided to 3types
Resting treg Cd45Ra +ve,foxp3 +ve
Activated treg cd45Ra -ve , foxp3+ve
Tr1 cd45Ra-ve, foxp3-ve
Reference:
Schmidt JV, Han JM, Macdonald KG, et al. The role of FOXP3 in regulating immune responses. Int Rev Immunol 2014;33:110-128
Trzonkowski P, Dukat-Mazurek A, Bieniaszewska M, Marek-Trzonkowska N, Dobyszuk A, Juscinska J, et al. Treatment of graft-versus-host disease with naturally occurring T regulatory cells. Biodrugs. (2013) 27:605–14.
Treg is one of CD4 T lymphocytes, generated in the thymus by exposure to self antigen .
Has a role in the T cell suppression by cytokines like IL-10 and by inhibtory membrane molecules like CTL-4.
It lead to peripheral tolerance .
High level of Treg prevent the rejection so we need to keep it high. They express the Foxp3 which indicates their activity and we can monitor them by measuring it.
It found to be had a great role in treating cancers and autoimmune disease
Dear Nazik
Thank you for your contribution
You could have expanded on the subtypes of Treg and the effect of immunosuppression on the Treg population.
You need to write with references.
Treg have a role in regulating and suppressing of the immune system Treg characterized by expression of both Cd4 T cells and CD 25 also expression of nuclear transcription factor FoxP3 ,their supprissive activity is achieved by contact dependent and independent mechanisms ,both simultaneously cause suppression of effector T cells through different Ag specificities or effect on T cells tolerance that recognize Ag also by effecting on CD4+ ,CD8+ T cells ,B cells macrophages dendritic cells and memory cells .
Different medications effect on Treg action either by inhibition or activation and increase survival :calcineurin inhibitorscause decrease proliferation and viability ,MMF variable effect ,steroid no effect on Treg activity ,mTOR inhibitors help to differentiation and proliferation and increase FoxP3 expression, using of alemtuzumab in induction help to generation and expansion of Treg while using of anti CD25(basiliximab) have adverse effect on Treg because of high expression of CD 25 on Treg also using low dose of recombinant IL-2 have dramatic effect on Treg expansion finally there are non immunosuppressive medications have effect on Treg like metformin cause increase Treg and erythropoietin effect on their proliferation also effect on T cells proliferation.
When tolerance occurs by the effect on Treg it should be monitored by different ways like,flow cytometry,programmed graft biopsy and DSA monitoring.
Thanks Tahani
References please.
CD4+ T cells are divided into regulatory T cells & conventional T helper cells. T helper cells control adaptive immunity against pathogens and cancer by activating other effector immune cells. regulatory T cells are defined as CD4+ T cells that suppress or regulate the effect of helper cells. ın other words Treg is a subgroup of suppressor T cells. although not specific to it, there are some markers for Treg cells. The most widely used markers for Treg cells are CD25, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR), lymphocyte activation gene-3 (LAG-3), CD127, and forkhead/winged-helix transcription factor box P3 (Foxp3). Their main effector cytokines include IL10, TGF-β, and IL35. IL10 has a potent inhibitory effect that suppresses pro-inflammatory response thereby limiting tissue damage initiated by the inflammatory process. the specific markers of thymic (tTreg) and peripheric (pTreg) are not well defined.
Recently, (Treg)s have been shown to suppress most immune cell types, including lymphocytes, various types of macrophages, dendritic cells, and also B cells. they have a very heterogenous proposed mechanism that may clarify their impressive effect on the effector cells though well not clearly identified. by expression of the inhibitory
molecule TIGIT they also inhibit Th1- and Th17-mediated pro-inflammatory immune
response .
I a small study in 2008 ( 10.1111/j.1600-6143.2008.02268.x.) FOXP3 was associated with rejection and unfavorable outcomes. but as this is not unique to Treq, this is still not clear
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784904/
https://www.hindawi.com/journals/jir/2012/925135/
https://www.frontiersin.org/articles/10.3389/fimmu.2019.03100/full
This is much better Mahmud
A. Regulatory T cells (Tregs) are a subset of CD4+ T cells that express the transcription factor Foxp3 and potently suppress many immune responses. It has been shown that Tregs are able to inhibit T cell proliferation and cytokine production and play a critical role in preventing autoimmunity. Different subsets with various functions of Treg cells exist. Dysregulation in Treg cell frequency or functions may lead to the development of autoimmune disease.
B. Self-tolerance is a state of unresponsiveness to self-tissues/antigens. Foxp3 + T-regulatory cells (Tregs) play an essential role in suppressing autoimmune responses directed against self-antigens and thereby regulate self-tolerance. “Natural” TREG comes directly from the thymus and helps maintain self-tolerance. Natural Tregs are differentiated in the thymus on the basis of their higher TCR-affinity to self-antigens and migrate to the periphery where they maintain peripheral tolerance. In addition, extra-thymic differentiation of induced Tregs can occur in the periphery which can control abrupt immune responses under inflammatory conditions. A defect in Treg cell numbers and/or function is found to be associated with the development of autoimmune disease in several experimental models and human autoimmune diseases.
C. Augmentation of Tregs has been shown to be beneficial in treating autoimmunity in preclinical models, and Treg-based cellular therapy has shown initial promise in clinical trials. The 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.
Reference:
1. Kondĕlková K, Vokurková D, Krejsek J, Borská L, Fiala Z, Ctirad A. Regulatory T cells (TREG) and their roles in immune system with respect to immunopathological disorders. Acta Medica (Hradec Kralove). 2010;53(2):73-7.
2. Kumar P, Saini S, Khan S, Surendra Lele S, Prabhakar BS. Restoring self-tolerance in autoimmune diseases by enhancing regulatory T-cells. Cell Immunol. 2019 May;339:41-49.
3. 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
Well done Fakhriya
What is the proposed mechanism(s) of induction of tolerance by Treg?
Tolerance is achieved once T reg out-number T effectors .normal T reg represent 5-10% of circulating t cells. This needs to be increased up to 33% to prevent rejection.2
T reg have many mechanism for suppression of immunity :1
1- Suppressive cytokines production like IL-10, TGF-β, and IL-35
2- Inhibit the maturity of denderitic cells and production of kynurenin
3- Secretion of granzymes which are cyto-lytic of T eff
4- Through CD39&CD73 catalyze the production of inhibitory adenosine
5- Through CD25 , catch IL-2 which is the growth factor of Teff
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- Vaikunthanathan T, Safinia N, Boardman D, Lechler RI, Lombardi G. Regulatory T cells: tolerance induction in solid organ transplantation. Clin Exp Immunol. 2017 Aug;189(2):197-210. doi: 10.1111/cei.12978. Epub 2017 May 25. PMID: 28422316; PMCID: PMC5508315.
Thanks Hinda
Well done. Short and sweet
T reg
T reg are suppressor CD4 T lymphocytes with high expression of both CD25 and transcription factor FoxP3. They are either natural T reg (thymus derived )or induced peripheral Tregs
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 .
T reg can be activated through TCR in response to
1- antigenic stimulation both self and non self antigens
2- Non antigenic stimulation in response to various cytokines
T reg are involved in maintaining tolerance via recognizing , suppressing or even eliminating allo- reactive cells . First , T reg are activated by stimulation of TCR via certain Ag ,then they start to recognize the allo-reactive cells against this certain Ag and they suppress both CD4+ and CD8 + T cells in non specific way (not only to this Ag but to other Ag specific cells also ) (1)
Till now , the most reliable marker for monitoring T reg is the transcription factor FOXP3. The levels of intragraft, prepheral and urine FOXP3 mRNA in transplant recipient suffering from DGF and acute rejection where significantly elevated , so FOXP3 represents a good marker for T reg activity but it also can be expressed also in nonregulatory T-cells upon activation. Also the number of Intragraft Treg appears to indicate graft rejection . Other markers to identify Treg including CD45RB , CTLA-4 , GITR , CD122, CD103, and galectin-10 and the absence of CD127 , are still underinvestigations.(2)
1- Hu, M., Wang, Y. M., Wang, Y., Zhang, G. Y., Zheng, G., Yi, S., O’Connell, P. J., Harris, D. C., & Alexander, S. I. (2016). Regulatory T cells in kidney disease and transplantation. Kidney international, 90(3), 502–514. https://doi.org/10.1016/j.kint.2016.03.022
2- Brown K and Wong W (2009). Monitoring Regulatory T-Cells after Transplantation: Is It Useful?.
Trends in Transplant ;3:119-28
What is Treg and how it is activated?
T reg are part ofCD4+T lymphocytes which concern of suppressing other t cells. It has role in prevention of autoimmune diseses . in transplantion, upregulation or infusion of t cell is supposed to be associated with induction of tolerance. 1
Activation of t reg occur through stimulation of either : CD3 and CD28 molecules or alloantigenic expressing APC. This stimulation require IL2 and rapamycin.1
T reg have TCR which when activated produce several molecules like IL-10, IL-35, TGF-β, and cAMP; expression of c oenzymes CD39 and CD73which will degrade ATP and kill APC.2
1-Edozie et al ,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- Qizhi Tang, Flavio Vincenti, Transplant trials with Tregs: perils and promises,J Clin Invest. 2017;127(7):2505-2512. https://doi.org/10.1172/JCI90598.
regulatory T cells (also called Tregs) are T cells which have a role in regulating or suppressing other cells in the immune system. Tregs control the immune response to self and foreign particles (antigens) and help prevent autoimmune disease. Tregs produced by a normal thymus are termed ‘natural’; nTreg. Treg formed by differentiation of naïve T cells outside the thymus, i.e. the periphery, or in cell culture are called ‘adaptive’ or inducible ; iTreg.
Natural Treg are characterised as expressing both the CD4 T cell co-receptor and CD25, which is a component of the IL-2 receptor. Treg are thus CD4+ CD25+. Expression of the nuclear transcription factor Forkhead box P3 (FoxP3) is the defining property which determines natural Treg development and function.
FoxP3 is crucial for maintaining suppression of the immune system. Naturally occurring mutations in theFOXP3 gene can result in self-reactive lymphocytes that cause a rare but severe disease IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked) in humans and scurfy in mice.
Tregs suppress activation, proliferation and cytokine production of CD4+ T cells and CD8+ T cells, and are thought to suppress B cells and dendritic cells. Tregs can produce soluble messengers which have a suppressive function, including TGF-beta, IL-10 and adenosine. Additional markers of natural Tregs are CD152 (CTLA-4) and GITR (glucocorticoid-induced TNF receptor), although it should be noted that these are also expressed by other T-cell types periodically (e.g. activated T cells) so they are not in themselves unequivocally diagnostic. However, the role of these markers on other T cells is not clearly defined[1]
The activation of Treg cells is antigen-specific, which implies that the suppressive activity of Treg cells is triggered in an antigen-specific fashion. A major challenge for the Treg field is to understand how Treg cells discriminate between the bad (i.e. self-reactive) Th cells, which should be suppressed, and the good (i.e. virus-specific) Th cells, which should not. If this distinction is not made, the host will be immunosuppressed and succumb to microbial infection or cancer.
Upon antigen exposure in the regional lymph nodes, Foxp3+ Tregs become activated and exert suppression at a much lower concentration of antigen than naive T cellsTreg cells are suggested to be autoreactive and to suppress conventional Th cells with the same antigen specificity. This allows Treg cells to mediate natural tolerance by ensuring self/non-self discrimination. The mechanism of suppression is proposed to be based on a three-partner interaction between the Treg cell, the Th cell to be suppressed, and the antigen-presenting cell (APC)[2]
Blocking costimulatory pathways can induce allograft tolerance in major histocompatibility complex (MHC) mismatched kidney transplant models. Recent studies showed that Foxp3+ Tregs were activated by blockade of B7-CD28 and CD40-CD40L pathways. In primates, the combination costimulatory blockade with CTLA4-Ig and anti-CD40L, anti-CD40 and anti–B7-2, or anti-CD40L, sirolimus, and a single donor-specific transfusion can significantly prolong renal allograft survival across an MHC mismatch.[3]
low-dose IL-2 therapy has been shown to selectively expand FOXP3
the frequency of Tregs was measured with flow cytometry
other method was used is measuring Il-10 secretion by ELISA
monitoring of circulating Tregs in peripheral blood is helpful for evaluating the immune status of kidney transplant recipients during the early post-transplant period, hence, it can be helpful for choosing immunosuppressive regimen [4]
[1] https://www.immunology.org/public-information/bitesized-immunology/cells/regulatory-t-cells-tregs
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784904/
[3] https://www.sciencedirect.com/science/article/pii/S008525381630076X
[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2633210/
Better to write references formally. Writing them as links needs a particular referencing style,
I agree with Dr Ala
What is Treg and how it is activated?
Treg is a subset of CD4+ T cells having regulatory or immunosuppressive actions. (1) They maintain immunological balance by providing immune tolerance against self-antigen and keeping immune reactions under control.
Treg activation is antigen dependent. The T cel receptor (TCR) engagement of the Treg by antigen leads to immune response suppression.
What is the proposed mechanism(s) of induction of tolerance by Treg?
There are multiple mechanisms of action of Treg, (2) These include:
a) Contact-independent anti-inflammatory cytokine (IL-10, IL-35 and TGF beta) production, and exosome formation leading to specific gene silencing, ultimately preventing T cell activation.
b) Contact dependent suppression through interaction of CTLA4 on Treg with CD80/86 on APC, restricting T cell access to signal 2 (due to higher affinity of CTLA4 than that of CD28).
c) Inducing apoptosis using Fas/FasL and Granzyme/perforin pathways.
d) Disruption of metabolic pathways via CD39, causing decreased ATP triggered proinflammatory signals. Tregs have increased intracellular cAMP which gets transferred to T effector cells leading to increased ICER (inducible cAMP early repressor), inhibit IL-2 transcription leading to low IL-2 causing apoptosis.
The CD8+ T cells are responsible for graft destruction by apoptosis due to cytotoxic activity.
How would you implement Treg monitoring in clinical transplantation?
Tregs can be monitored in clinical transplantation by the specific markers related to Treg including FOXP3, CD25, CTLA4, GITR and CD127. (3) These markers are T cell activation markers, hence they are not specific for Treg.
Tregs have been used in clinical trials in transplantation as a way to induce tolerance. Deuterium labelled pTregs have been used in kidney transplant recipients. (4) Post transfusion, these could be tracked by their deuterium signals. Similarly, Indium labelled T regs have also been transfused in kidney transplant recipients and monitored using SPECT. (5)
References:
1) Issa F, Schiopu A, Wood KJ. Role of T cells in graft rejection and transplantation tolerance. Expert Rev Clin Immunol 2010;6:155-169.
2) Vaikunthanathan T, Safinia N, Boardman D, et al. Regulatory T cell: tolerance induction in solid organ transplantation. Clin Exp Immunol 2017;189:197-210.
3) Corthay A. How do regulatory T cell work? Scand J Immunol 2009;70:326-336.
4) Chandran S, Tang Q, Sarwal M, et al. Polyclonal regulatory T cell therapy for control of inflammation in kidney transplants. Am J Transplant 2017;17:2945-2954.
5) Hutchinson JA, Riquelme P, Sawitzki B, et al. Cutting Edge: Immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients. J Immunol 2011;187:2072-2078.
Well done, Amit
Regulatory T cells (Tregs) :
have been shown to be important in maintaining immune homeostasis and preventing autoimmune disease, including autoimmune kidney disease. It is also likely that they play a role in limiting kidney transplant rejection and potentially in promoting transplant tolerance. Although other subsets of Tregs exist, the most potent and well defined Tregs are the Foxp3 expressing CD4+ Tregs derived from the thymus or generated peripherally.
Are a subset of CD4+ T cells that express the transcription factor Foxp3 and potently suppress many immune responses.
There are more than 1 type
_ NATURAL : express CD 25
_ INDUCABLE :
_ TR 1 REGULATORY CELLS :
IL 10 PRODUCER
IL 17
OTHERS ARE CD8 TREG
References from
https://www.karger.com/Article/FullText/490703
https://doi.org/10.1016/B978-012455900-4/50289-0
●ACTIVATED BY :
Tregs are activated by expression of the transcription factor FoxP3, which appears to be a “master” gene for the development and function of this type of T LYMPHOCYTE.
● Establishing tolerance to an allograft has become an area of intense study and would be the ideal therapy in clinical practice.
The discovery of a subset of T cells naturally committed to perform immunoregulation has led to further investigation into their role in the immunopathogenesis of transplantation.
Evidence suggests that regulatory T cells (Tregs) are fundamentally involved in promoting allograft tolerance.
Efforts to characterize specific markers for Tregs, while challenging, have identified Foxp3 gene expression as a crucial step in promoting the tolerance inducing features of Tregs.
●●●
MONITORING BY:
CD4+CD25+ και CD4+CD25+FoxP3+ Τ lymphocytes CAN BE measured, by flow cytometry
BEFORE renal transplantation & after it by 3 months.
September 2020 – Volume 104 – Issue S3 – p S311
doi: 10.1097/01.tp.0000700084.83497.0e ●●●●●●●●●●●●●●
Some EXTRA information about TREG :
● Tregs are important in countering the development of allergic and autoimmune disease, as FoxP3 mutant mice and humans develop airway inflammation, eosinophilia, and elevated serum IgE levels.
●Tregs have also been implicated in the prevention of graft rejection and graft versus host disease (GVHD
☆☆The discovery of a subset of T cells naturally committed to perform immunoregulation has led to further investigation into their role in the immunopathogenesis of transplantation.
☆☆Organ transplantation is considered the ultimate therapy for end-stage organ disease.
While pharmacologic immunosuppression is the mainstay of therapeutic strategies to prolong the survival of the graft, long-term use of immunosuppressive medications carries the risk of organ toxicity, malignancies, serious opportunistic infections, and diabetes.
●Therapies that promote recipient tolerance in solid organ transplantation are able to improve patient outcomes by eliminating the need for long-term immunosuppression.
●●●●●●●
FURTHER INFORMATION ABOUT TREG:
A number of approaches, including those based on targeting the glycogen synthase kinase 3β signaling pathway or activating the melanocortinergic pathway, have been tested as a way to promote Treg lineage commitment and maintenance as well as to facilitate immune tolerance.
In order to be effective in clinical practice, Tregs must be allospecific and possess a specific phenotype to avoid suppression of other aspects of the immune system or increasing the risk of malignancy or infections.
Multiple experimental and clinical studies have demonstrated the impact of currently used immunosuppressants on the immunoregulatory activities of Tregs and their Foxp3 expression status.
Pharmacological induction of tolerogenic Tregs for inducing transplant tolerance, including epigenetic therapies, is in the ascendant.
—-> Therapies that promote Treg function and survival may represent a novel strategy for achieving immune tolerance in transplant patients <—-
Treg are specialized T cells ( Subtype of CD4 T cells ) that inhibit deleterious immune response of the conventional T helper cells as they prevent T cell proliferation and cytokine production .
They help to maintain homeostasis and tolerance
**Functions of T regs include :
1.Prevention of autoimmune diseases by maintaining immunologic self-tolerance .
2.Suppression of allergy and asthma .
3.Induction of tolerance against dietary antigens ( oral tolerance )
4.Induction of maternal tolerance to the fetus
5.Suppression of pathogen-induced immunopathology .
6.Regulation of the effector class of the immune response .
7.Suppression of T-cell activation triggered by weak stimuli .
8.Feedback control of the magnitude of the immune response by effector Th cells .
9.Protection of commensal bacteria from elimination by the immune system .
** activation of T regs occurs through antigen specific manners , and so their suppressive effect on T helper cells is antigen dependent
Whether the same antigen activates both T helper and TRegs or not , it is believed that T regs can suppress T helper cells of different antigenic specificities , but it’s effect is more potent and relevant when both have same antigen specificity .
during maturation in the thymus gland , Treg cells would be generated with a high affinity TCR for a self peptide.
And so they are self reactive and help to suppress immune response to self antigens and maintain tolerance
An important discovery in the field of Treg therapy in humans is the finding that Tregs can be isolated and expanded in vitro while maintaining immunoregulatory function.
Studies showed that infusion of Tregs has the potential to induce long-term donor-specific tolerance without interfering with immune responses to pathogens and tumors in transplant patients.
Treg therapies have proved efficacy in alloimmune responses in the settings of graft-versus-host disease (GvHD), as well as organ and cell transplantation in animal models.
Molecular markers of Treg markers include : CD25, CTLA-4, GITR, CD127, LAG-3 and Foxp3
There is growing evidence that all of the appear to be general T-cell activation markers.
This observation strongly suggests that T-cell activation is required for T-cell mediated suppression.
Corthay A. (2009). How do regulatory T cells work?. Scandinavian journal of immunology, 70(4), 326–336. https://doi.org/10.1111/j.1365-3083.2009.02308.x
One of the critical functions of the immune system is to prevent responses directed toward self-antigens. It is achieved during two processes, central (in the thymus) and peripheral (extrathymic lymphoid tissue) tolerance. Treg in humans are CD4+ T lymphocytes that express high levels of CD25 and the transcription factor FOXP3. It is now clear that FOXP3 does not function alone and that other molecular mechanisms such as DNA epigenetic modification and expression of additional transcription factors are required to induce highly stable, functional Tregs.
Mechanisms of tolerance were described as recessive tolerance and dominant tolerance. Recessive tolerance mechanisms depend on clonal deletion and anergy. The term recessive refers to the fact that all self-reactive T cells need to be physically eliminated or functionally inactivated. In contrast, dominant tolerance depends on suppressive action of regulatory cells and can therefore be transferred from tolerant to naïve individuals.
It is illustrated that elimination of CD25+FOXP3+ CD4+ T cells (Treg) unleashed a latent autoimmune potential in the normal T cell repertoire. Approximately 80% of Treg cell repertoire originate from the thymus (thymus derived Treg cells) where FOXP3+ Treg cell differentiation can be instructed by encounter of agonist self-antigens. Thus, recognition of self during thymocyte differentiation not only leads to clonal deletion, but also specifies diversion of cells into self-reactive T cell lineage that lacks autoimmune potential, and instead confers tolerance through immune regulation. Simple models that explain different outcomes of self-antigen recognition in the thymus are based on the affinity and/or avidity of the underlying TCR-peptide-MHC complex interactions. T cell signals crucially impact the cell fate decisions of thymocytes.
The term affinity describes the strength of a single interaction between TCR and it’s peptide-MHC ligand, where as the term avidity is proportional to the multiplicity of such interactions.
According to an affinity-based model of thymocyte development, at a given fixed density of cognate peptide-MHC in the thymus, T cells bearing the highest affinity TCRs are removed from the repertoire by clonal deletion, whereas T cells bearing TCRs of intermediate affinity are diverted into Treg cell repertoire. T cells bearing TCRs of low affinity escape into the periphery as conventional T cells (at a fixed level of neo-self-antigen expression, the efficiency of Treg cell selection was directly correlated with the reactivity of different TCRs).
An avidity-based model posits that in addition to the TCR affinity, the density of the peptide MHC ligand is also crucial. At a given fixed TCR affinity, increasing or decreasing the density of antigen presented on thymic antigen-presenting cells will lead the cell fate towards either clonal deletion or Treg cell differentiation, respectively. Several observations are consistent with this model. First, TCR-transgenic models have shown a clear correlation between antigen expression levels and the ensuing cell fate. Second, the titrated administration of agonist peptide to TCR-transgenic fetal thymic organ cultures or through intravenous injection into adult mice revealed a positive correlation between agonist concentration and the number of Treg cells; above a certain threshold, further increasing the peptide dose resulted in thymocyte deletion. Third, at fixed levels of antigen expression, attenuating cognate antigen presentation through the knockdown of MHC class II expression resulted in decreased clonal deletion and increased emergence of Treg cells. Finally, low-affinity or high-affinity peptide ligands for the same TCR can instruct Treg cell differentiation with equal efficiency provided that the density of the low-affinity ligand is correspondingly higher.
The process of negative selection (deletion of T lymphocyte with undesirable activity) is not perfect in the thymus, and the autoreactive T lymphocytes, which escape from negative selection, can be found in the periphery and prevented by the process of peripheral tolerance. The process of peripheral tolerance and regulation can lead to the generation of regulatory T cells (induced or peripheral Treg).
Regulatory lymphocytes suppress autoimmune reaction and prolong allograft survival. They suppress immune responses by different mechanisms including cytokines (IL 10, TGF β) and inhibitory membrane molecules (CTLA-4), and by the release of adenosine through the CD39-CD73 pathway.
Several studies in kidney transplantation have shown a positive correlation between the presence of Treg cells and good clinical outcome.
The role of Treg cells in the prevention of graft rejection and the induction and maintenance of allograft tolerance is clearly demonstrated. The presence of intragraft FOXP3 Treg cells was associated with an overall donor-specific hyporesponsiveness of T cells toward alloantigens and expansion of peripheral CD25+FOXP3+ T reg in patients and as well as favorable graft outcome.
The reports also demonstrated higher frequencies of circulating Tregs in tolerant patients. Interestingly, an increase in mTregs was found uniquely in operationally tolerant patients compared to other transplant recipients and healthy donors.
Expanding the Treg population and shifting the immune balance in favor of the regulatory cells has been proposed as a strategy to potentially minimize the need for effector immunity control, reduce immunosuppression requirements, and induce tolerance. In small animal studies, CD4+CD25+FoxP+Treg have been infused to effectively prevent acute and chronic rejection.
The studies that introduced protocols for mixed chimerism have demonstrated that combined kidney and stem cell transplantation using an engineered cellular product enriched in hematopoietic stem cells and tolerogenic graft facilitating cells was able to promote graft tolerance in mice by increasing Tregs.
Another important aspect of Tregs in human kidney transplantation is the influence of immunosuppressive treatment. An increase or decrease in circulating/intragraft Tregs could be the consequence of certain suppressive therapies. About CNIs, they provided conflicting results. Some studies have shown negative effects of CNIs on the expression of Treg cells and others have demonstrated enhancement of Treg function using clinically relevant doses of CNIs. It seems that these discrepancies may be due to different dose-dependent effects of the drugs. In contrast to CNI, inhibitors of the mTOR pathway are well-established pro-Treg factors, and can increase and stabilize Treg phenotype and suppressive functions, notably by maintaining a complete demethylation of FOXP3.
Ludger Klein1*, Ellen A. Robey2 and Chyi-Song Hsieh3. Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation, NATuRe RevIewS | IMMunology, volume 19 | JANUARY 2019
F. Braza1,2,3, M. Durand1,2,3, N. Degauque2,3 and S. Brouard, Regulatory T Cells in Kidney Transplantation: New Directions? American Journal of Transplantation 2015; 15: 2288–2300
Nahel Elias, A. Benedict Cosimi, and Tatsuo Kawai, Clinical trials for induction of renal allograft tolerance, Curr Opin Organ Transplant 2015, 20:406–411
Dear All
What is the relation between Treg and acute rejection?
Treg are the T cells responsible for immune response suppression. Hence in the clinical situation with low Treg, there is high chance of acute rejection.
small animal studies, CD4+CD25+FoxP+Treg have been infused to effectively prevent acute and chronic rejection
High level of Treg prevent rejection because it suppress the immune response
Treg
Tregs are CD4+CD25 high T lymphocytes expressing FoxP3 transcription factor either constitutively (thymic Tregs or tTregs) or after peripheral recognition of antigens (peripheral Tregs or pTregs).
Role of Tregs In addition to their (i) role in self-antigen tolerance, both Treg subsets can (ii) suppress inflammatory alloreactive T cells in vitro and in vivo. They(iii) inhibit alloreactivity in MLR in vitro and are thought to (iv) mediate transplant tolerance elicited via leukocyte costimulation blockade, donor-specific transfusion.
Proposed mechanism(s) of induction of tolerance by Treg :
Implementation of Treg monitoring in clinical transplantation:
– What is T reg ?
T regulatory cells are a specified subpopulation of T cells which suppress immune response, so that homeostasis and self-tolerance are maintained .(1)
Tregs are divided in subpopulations according to the differentiation sites and the expression of functional markers, inspite of this there is overlap between these parameters. (2)
– how it is activated?
In the thymus, thymically derived Treg( tTregs,) are developed serving as an insurance to prevent self-autoreactivity
Foxp3 is the lineage-specifying transcription factor of Tregs, whose deficiency can cause fatal autoimmune disease.
Rudensky et al mentioned that the conserved noncoding sequence (CNS)1 of the Foxp3 gene, is critical for the generation of induced press but dispensable for tTreg development.
Precautions must be taken to ensure the identity and stability of Tregs for translation in clinical use although it has great therapeutic potential for curing autoimmune diseases and preventing unwanted immune responses such as graft-versus-host disease.(3)
tTregs and induced T reg (iTregs) play different roles in different tissues. iTreg differentiation induced by non-self- antigens and a particular TCR signaling combined with other signals ,these cells are more functional for maintaining mucosal tolerance. iTregs may control immune responses to commensal antigens and prevent allergic-type reactions.(2)
-Induction of tolerance ?
Tregs regulate immune responses and tolerance in multiple ways,
possibly Tregs have a memory phenotype expressing high levels of effector memory markers, including IL-7R (CD127), CD44, and CD27 . (3)
Tregs elicit a direct response on a target cell, or indirect, in which a third-party cell is affected and suppresses the target cell .
Tregs can influence changes in the microenvironment due to expression of CD25, this receptor in high levels enables it to uptake more IL-2 and “starve” the surrounding cells of this cytokine.
Also NKs is directly affected by Tregs in a membrane bound TGF-ß dependent manner. Tregs have a direct effect on B-cells via PDL1/PD-1 interaction and DCs.
Tregs suppress CD4 T cell activation and proliferation by contact-dependent and contact-independent mechanisms .
Tregs can also influence proliferation, activation and apoptosis of CD8+ T cells.(2)
-T reg in transplanation?
The possibility of Treg isolation, expansion and infusion in kidney transplant recipients on immunosuppression with subclinical graft inflammation was tested . Three kidney transplant recipients were enrolled They received a single infusion and were maintained on tacrolimus, mycophenolate mofetil and prednisone and they were followed ,The authors showed that infused Tregs peaked in circulation the first week which were detectable during the first month after infusion ,dropping near the detection limit at 3 monthsafter wards with no increased incidence of infection nor malignany within 1 year of follow up but referring to the low number of the included patients, it was not possible toexpress any conclusion of either safety or efficacy of Treg infusion isolated from kidney transplant recipients.
Multiple clinical trials using Tregs to prevent rejection in solid organ transplantation are still going on and results are pending, but some studies demonstrated preliminary the capability of Tregs to treat autoimmune diseases and prevent graft rejection. In fact it will take time for it to be implemented in practice .(2)
1-Kondelkova K et al. Regulatory T cells (TREG) and their roles in immune system with respect to immunopathological disorders .Acta Medica (Hradec Kralove)2010;53(2):73-7.
2- Romano M.etal al . Past, Present, and Future of Regulatory T Cell Therapy in Transplantation and Autoimmunity .Front. Immunol., 31 January 2019.
3-Zhang Z etal . Activation and Functional Specialization of Regulatory T Cells Lead to the Generation of Foxp3 Instability .J Immunol 2017; 198:2612-2625.
Treg cells
Regulatory T cells (Treg) are a subset of CD4+ T cells which have a role in regulating or suppressing other cells in the immune system. they control the immune response to self and foreign antigens and help prevent autoimmune disease.
they express both the CD4 T cell co-receptor and CD25, which is a component of the IL-2 receptor and express the transcription factor forkhead box P3 protein (FOXP3)
The activation of Treg cells is antigen-specific
Treg can generated either in thymus during negative selection(natural Treg) or in the periphery (induced Treg cells).
Regulatory T cells are major contributors to peripheral tolerance:The immune system uses many mechanisms to maintain immunologic self-tolerance and protect the host against exacerbated responses to foreign antigens. The existence of regulatory T cells [Tregs] that actively suppress the function of conventional T cells is a key mechanism by which the immune system limits inappropriate or excessive responses.
Tolerance is a state of unresponsiveness in which the lymphocytes remain alive but cannot exert effector functions against a particular antigen.
There are two types of tolerance:
Mechanisms of peripheral tolerance:
1.Induction of anergy (a state of inactivation in which the lymphocytes remain alive but are unable to respond to antigen).
2.Deletion of autoreactive T cells via apoptosis.
3.Development of induced regulatory T cells (Tregs) which have similar effector functions as natural T regulatory cells, but they are produced in the periphery rather than in the thymus.
Flow cytometric analysis can detect Tregs in peripheral blood, spleen, draining lymph nodes (LN) and allograft tissue.
Malhotra, Deepali; Linehan, Jonathan L. Tolerance is established in polyclonal CD4+ T cells by distinct mechanisms according to self-peptide expression patterns. Nature Immunology.2016: 17 (2): 187–195.
Cretney, Erika; Kallies, Axel; Nutt, Stephen L. “Differentiation and function of Foxp3+ effector regulatory T cells”. Trends in Immunology.2013: 34 (2): 74–80.
Workman CJ, Szymczak-Workman AL, Collison LW, Pillai MR, Vignali DA. The development and function of regulatory T cells. Cell Mol Life Sci. 2009;66(16):2603-2622.
Corthay A. How do regulatory T cells work?. Scand J Immunol. 2009;70(4):326-336.
What is Treg and how it is activated?
Treg cells are subtype of T lymphocytes responsible for regulation and adjustment of immune response due to its ability to suppress other types of effector cells
Tregs may develop in the thymus (tTregs), as well as and peripherally (pTregs) from effector cells.
tTregs express FoxP3 constitutively and have a T cell receptor (TCR) of relatively high autoaffinity. These cells are predominant in the bloodstream and in the lymph nodes; they are mainly involved in providing tolerance to autoantigens .
Peripherally, CD4+-effector cells affected by IL-2 and TGF-β may under certain conditions begin to express FoxP3, thus becoming functional equivalents of tTregs .
Mechanism of action
Tregs have been shown to suppress most immune cells including lymphocytes, various types of macrophages, dendritic cells and B cells .
Treg suppressive activity against a specific T effector population may be associated with the expression of transcription factors typical of this subpopulation;
Tregs are believed to acquire the expression of transcription factors typical of effector cells owing to their adaptation to the immune response being polarized toward Th1, Th2, or Th17.
• expression of T-bet, a Th-1-associated transcription factor, in Tregs is related to the expression of the inhibitory molecule TIGIT, which binds CD155 to dendritic cells to increase the production of IL-10 and reduce that of IL-12 in the dendritic cell, thus inhibiting the activation of T effectors .
•Tregs with the T-bet+TIGIT+ phenotype selectively inhibit the Th1- and Th17-mediated proinflammatory immune response .
• Th2-associated transcription factor IRF-4 enables Treg expression of ICOS and CTLA-4; along with JUNB and RBPJ, it is needed to limit the Th2-mediated immune response .
•expression of the Th17-typical factor STAT3 in Tregs is closely related to the regulation of the Th17-mediated immune response and enables the expression of IL-10, Ebi3, granzyme-B, and perforin-1 genes .
•Antigen-specific suppression is mainly caused by the direct Treg–DC (dendritic cell) interaction enabled by the specific recognition of the antigen (Ag) the DC presents as part of MHC-II by Treg TCR results in inducing an Ag-specific tolerogenic dendritic cell or rendering the DC unable to present a specific antigen.
•Antigen-non-specific mechanisms include the enzymes CD39/CD73 on the Treg surface, which cause ATP to degrade to adenosine. Increased adenosine concentration in the microenvironment inhibits DC presentation of antigens and suppresses the proliferation of activated T effectors .
•Another non-specific suppression factor is the Treg production of cytokines: TGF-β, IL-10, and IL-35.They can suppress the activation and proliferation of effector T and B lymphocytes; they can also directly induce pTregs and Bregs (75–78). In addition, TGF-β and IL-10 inhibit antigenic presentation to stimulate the generation of tolerogenic dendritic cells, which in their turn enable pTreg induction .
Daniil Shevyrev and Valeriy Tereshchenko.
Treg Heterogeneity, Function, and Homeostasis.
Front. Immunol.(2020 ).
How would you implement Treg monitoring in clinical transplantation
immunosuppression that used as tacrolimus, MMF % mehtylprednisolon can affect viability & proliferation of Treg in dose dependent manner
TRACT trial
The TRACT trial utilised ex vivo expanded polyclonal Treg cells infused in a dose‐escalation manner at the end of the expansion period. this trial reported no cases of opportunistic infections or rejection after the infusion of polyclonal Treg cells in patients undergoing de novo kidney transplantation.
TASK trial
TASK trial from UCSF focussed on utilising polyclonal Treg cells to modulate subclinical inflammation in the renal allograft.
Other trials are ongoing with promising results.
Muhammad Atif, Filomena Conti.Regulatory T cells in solid organ transplantation.
Clin Transl Immunology. 2020; 9(2): e01099.
You all agree that Tregs are CD25 +ve cells.
it is alpha chain IL-2 receptor which is expressed on activated T cell and has high affinity to IL-2, and expressed on Treg cells
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.
Akiko Furukawa, Steven A. Wisel, Qizhi Tang. Impact of immune-modulatory drugs on Treg. Transplantation. 2016 Nov; 100(11): 2288–2300.
-Natural CD25+CD4+ Tregs are engaged in suppression of autoimmune disease, its depletion leads to the development of autoimmune disease in rodents. (1)
– CD25, is the α-chain of the interleukin 2 (IL-2) receptor, is expressed on activated T cells which could be a therapeutic target.
Murine MAbs to human CD25 were used for prevention of renal allograft rejection.
2 of them ; basiliximab (Simulect)] and daclizumab [Zenapax])—were effective as part of induction regimens to prevent organ allograft rejection, and as induction therapies in organ transplantation and for treatment of established rejection.
Also a tolerance-promoting activity of anti-CD25cannot be established because CD25 is expressed on a subset of T-cells with regulatory/suppressor capacities that are critical in maintaining immune tolerance(2)
–CD4+CD25+ Tregs exhibit an anergic phenotype in vitro , failing to proliferate or produce interleukin (IL)-2 following antigen-specific stimulation, although they can stimulate vigorous antigen-dependent proliferative responses in vivo. IL-2 appears to play a crucial role in CD4+CD25+ Treg development and peripheral activity.This physiologic proliferation, in response to self-antigens, may be a main part of CD4+CD25+ Treg-mediated dominant tolerance as treatment of mice with a neutralizing anti-IL-2 monoclonal antibody prevents CD4+CD25+ Treg proliferation, leading to a reduction in their number, and development of organ-specific autoimmune disease . (3)
1-Wing K et al . Regulatory T cells .Clinical Immunology (Third Edition), 2008.
2-Chatenoud L . Emerging Therapies for Autoimmune Diseases .The Autoimmune Diseases (Fourth Edition), 2006
3-Read S etal .Regulatory T Cells.The Autoimmune Diseases (Fourth Edition), 2006
Thank you
1. What is CD25?
CD25 is alpha chain IL-2 receptor present on activated T cells. IL-2 acts on this receptor leading to clonal expansion of T cells.
2. What induction agent blocks CD25?
Anti CD25 induction agents include Basiliximab and Daclizumab.
3. How this blockage of CD25 affects Treg cells and the activated T cells response?
Anti CD25 agents use leads to aberrant pro-inflammatory T cell response due to CD25+ T cell depletion. Although it has been shown that Treg cells maintain their suppressive effects even in presence of CD25 blockade.
Reference:
Huss DJ, Pellerin AF, Collette BP, et al. AntiCD25 monoclonal antibody Fc variants differentially impact regulatory T cells and immune homeostasis. Immunology 2016;148:276-286.
Excellent
How do we maintain the balance between Tregs and Th17 cells? What are the consequences of shifting the balance toward Th17 cells?
FoxP3 cells
Fox3p is the transcription nuclear factor expressed on CD4+CD25+ Treg to induce its inhibitory immune response and it is responsible for this function of Treg so it is Treg marker
naiive CD4 cells give rise to Treg and Th17 under effect of TGF beta, IL-6, and all trans-retinoic acid , they have an opposing function, the balance between both will be affected by many factors like cytokines released from intestinal microbiome and also commensal bacteria and its metabolites…
Sara Omenetti and Theresa T. Pizarro. The Treg/Th17 Axis: A Dynamic Balance Regulated by the Gut Microbiome. Front. Immunol., 17 December 2015.
Th17 and Treg share a common pathway, medaited by TGF beta. In the presence of pro-inflammatory signals (IL-6, IL-21), CD4+ T cells give rise to Th17 cells and in the absence of proinflammatory signals, Treg formation takes place.
The balance between the 2 depends on a number of factors like TGF beta, IL-6, m-TOR signal, segmented filamentous bacteria, glycolysis, lipogenesis nudging towards Th17, while TGF beta with IL-2, CD28 signal, FOXp3 tilt the balance towards Treg.
So if the balance shifts towards Th17, it will lead to pro-inflmmatory conditons, with increased chances of rejection.
Reference:
Lee GR. The balance of Th17 versus Treg cells in autoimmunity. Int J Mol Sci 2018;19:730
Excellent, thank you
Regulatory T cells (Treg )are a specialized subpopulation of T cells that act to suppress the immune response. It can inhibit T cells proliferation, cytokine production by T cells, and suppress B cells and dendritic cells.
-The most specific marker for these cells is FoxP3, which is localized intracellularly. They are either arise in the thymus (Treg) or develop from peripheral CD4+ and express both CD4 and CD25)( that convert into CD4+FOXP3+Treg as peripherally derived Treg (pTreg).
-Their activation is antigen-specific.
– Treg was identified by flow cytometry.
-Memory Tregs are more potent than naiive Tregs.
– The suppressive function of Treg include direct cell contact 1 and regulatory cytokines such as TGF-β and IL-10 .2.3
-TGF-β is a crucial cytokine in inflammatory and mediating tolerance of allograft .,4,5,6.CD25 and class II MHC are the most common markers for Treg and are essential for transferring tolerance.7,8
-Effect of currently used immunosuppressant on Treg :
-potentiate Treg expansion eg ,ATG,almetzumab
-preserve suppressive activity and prolonged survival of Treg eg, corticosteroid
-Inhibit Foxp 3 expression and suppress Treg function in vivo and vitro eg, CNI
-promote Treg survival and function and augment Treg suppressive activity in vivo and vitro eg,mTOR
-Treg numbers can be increased through a direct infusion of Tregs or by promotion of the expansion of endogenous Tregs.
-In transplantation Tregs direct infusion is commonly used.
-The excellent early outcome result and low rejection rate of Kidney transplants make it nearly impossible to test the ability of Treg to prevent rejection when delivered at the time of transplantation 9. So, it is more challenging to design informative Treg therapy trials in kidney transplantation.
References
1.H. von BoehmerMechanisms of suppression by suppressor T cellsNat Immunol, 6 (2005), pp. 338-344
2. C.I. Kingsley, M. Karim, A.R. Bushell, et al.CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses J Immunol, 168 (2002), pp. 1080-1086
3. Z. Fehervari, S. SakaguchiDevelopment and function of CD25+CD4+ regulatory T cellsCurr Opin Immunol, 16 (2004), pp. 203-208
4.M. Saraiva, A. O’Garra The regulation of IL-10 production by immune cells Nat Rev Immunol, 10 (2010), pp. 170-181
5.J. Andersson, D.Q. Tran, M. Pesu, et al. CD4+ FoxP3+ regulatory T cells confer infectious tolerance in a TGF-beta-dependent manner J Exp Med, 205 (2008), pp. 1975-1981
6.W. Chen, W. Jin, N. Hardegen, et al.Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3 J Exp Med, 198 (2003), pp. 1875-1886
7. Waight JD, Takai S, Marelli B, Qin G, Hance KW, Zhang D, et al: Cutting edge: epigenetic regulation of Foxp3 defines a stable population of CD4+ regulatory T cells in tumors from mice and humans. J Immunol 2015; 194: 878–882.
8.Green DR, Flood PM, Gershon RK: Immunoregulatory T-cell pathways. Annu Rev Immunol 1983; 1: 439–463.
9. Matas AJ, et al. OPTN/SRTR 2013 Annual Data Report Kidney. Am J Transplant. 2015;15(suppl 2):1–34.
Well done
Foxp3 is a marker expressed in the Treg
And the Treg. Cells can classify to FOXp3 low expression Resting Treg while Treg cell with high FOXP3 expression. Called effector[ eTreg ] both Types Have immunosuppressive activity in vitro Also rTreg cells can proliferate and differentiated into eTreg cells after TCR activation and the eTreg are anergic and prone to apoptosis
While the CD45RA FOXP3 low expression nonTerg cells have no immunosuppressive and express the proinflammtory cytokines like IL-17,IL-2 and interferon -¥
rTreg cells have the subset of specific reprogramming to control different immune responses and it’s effect. Dynamic
One more about the importance of stability and plasticity of FOXP3 Treg cells
Some Foxp3 T cells may lose foxp3 expression and acquire effector Th cell function under certain inflammatory conditions
Adoptive transfers of Foxp3 T cells consider instable , 50% of the donor cells bacame foxp3 T cells and converted to IFN-¥ , IL 17 IL 2 producing cells
Modification. Of foxp3 are consider potential Therapeutic target for inflammation .Inhibitors of foxp3 positive regulators could be used to activate the immune system through the down regulation of the immunosuppressive activity of Treg while inhibitors for foxp3 negative regulators could be used to put brake on immune responses through. Up-regulations the immunosuppressive function of T reg cells .
References
FOXP3 regulatory T cells and their functional regulation
Cellular and molecular immunology 2015’12,558-565
Excellent response. More attention to writing style would add a lot.
Regulatory T cells (Tregs) are a subset of T cells that suppress immune activation and limit autoimmunity in the periphery (7).
A number of cell types with immune-regulatory function have been characterized as Tregs, though the one best understood, at present, are the CD4+FOXP3+ Tregs. These either arise in the thymus (Tregs) or develop from peripheral CD4+ T cells that convert into CD4+FOXP3+ Tregs as peripherally derived Tregs (pTregs).
Previously, it had been thought that peripheral tolerance due to either Tregs or pTregs would be insufficient for long-standing tolerance. However, increasing understanding of Tregs and other regulatory subsets has led to the possibility that transplant tolerance allowing reduction or cessation of immunosuppression could be achieved using regulatory cell subsets.
Tregs have been studied as a potential therapeutic in human solid organ transplantation. Sixteen Treg clinical trials that have focused on feasibility, safety and preliminary efficacy of infused Tregs to reduce the dose of calcineurin inhibitor (CNI)-based immunosuppression have been reported.
However, the majority of reported clinical trials using Tregs lack the capacity to robustly identify mechanistic effects and much of our understanding of underlying mechanisms relies on extrapolation of results from rodent and non-human primate studies.
Autologous or donor-derived peripheral blood is the most common source of Tregs used in clinical trials, although alternate sources such as umbilical cord blood and paediatric thymus, non-lymphoid tissue such as skin, adipose tissue and muscle have been explored.
Peripheral blood contains only a small proportion of Tregs that require purification via CD25+ cell selection, with or without CD8+ depletion.
Ex vivo expansion of these naturally-occurring Tregs can be achieved through various means, but the choices are dependent on whether polyclonal or donor allo Ag-reactive Treg (darTreg) is required.
darTregs are theoretically more potent, however, the majority of trials have expanded polyclonal Tregs with a combination of IL-2 and anti-CD3/CD28 magnetic bead stimulation ± rapamycin or TGF-β, although this process may require a greater cell infusion dose to achieve donor-specific suppressive effects.
Spence A, Klementowicz JE, Bluestone JA, Tang Q. Targeting Treg Signaling for the Treatment of Autoimmune Diseases. Curr Opin Immunol (2015) 37:11–20. DOI: 10.1016/j.coi.2015.09.002
Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S, et al. Regulatory T Cells: Recommendations to Simplify the Nomenclature. Nat Immunol (2013) 14(4):307–8. DOI: 10.1038/ni.2554
Putnam AL, Safinia N, Medvec A, Laszkowska M, Wray M, Mintz MA, et al. Clinical Grade Manufacturing of Human Alloantigen-Reactive Regulatory T Cells for Use in Transplantation. Am J Transplant (2013) 13(11):3010–20. DOI: 10.1111/ajt.12433
Thank you
“Tregs have been studied as a potential therapeutic in human solid organ transplantation. Sixteen Treg clinical trials that have focused on feasibility, safety and preliminary efficacy of infused Tregs to reduce the dose of calcineurin inhibitor (CNI)-based immunosuppression have been reported.
However, the majority of reported clinical trials using Tregs lack the capacity to robustly identify mechanistic effects, and much of our understanding of underlying mechanisms relies on extrapolation of results from rodent and non-human primate studies.”
Would you please elaborate more and add references on the therapeutic uses of Tregs?
CD4 T cells divided into Treg & Th cells( Treg function is to suppress dangerous activity of Th cells).In 1995 was the first time when a special phenotype of CD4 T cells in thymus (which have high level of IL-2R( CD25) & Foxp3) discovered . Since that several studies proved the importance of Treg cells in monitoring of immune homeostasis & prevention of autoimmunity. It can generated from thymus or peripheral T cells. Several functions of Treg are proposed in last decade as:
T reg cells can suppress immune response through different mechanism:
There are different studies aimed to decrease using of immunosuppressants , so Reg cells may be good solution to control immune response & induce transplant tolerance.
In 2017 phase I pilot study was done & its aim was to test the capability of isolation, expiation & infusion of Treg cells to renal transplant recipients, but due to low number of patients the safety of the infusion of Reg is not possible. Another phase I study started in 2018 that infuse Treg cells to recipients show increase the number of Treg after infusion comparing to control group & decide to precede to phase II trial.Most of the studies that use Treg to prevent rejection in solid organ transplantation are still not finished. Also it shown that immunosuppression that used as tacrolimus, MMF % mehtylprednisolon can affect viability & proliferation of Treg in dose dependent manner. For this reason several studies are try to find the best time for Treg infusion.
References:
1.Romano M., Fanelli G., Albany C., et al. Past, Present, and Future of Regulatory T cells Therapy in Transplantation and Autoimmunity. Front. Immunol. 2019, 10:43.
2 Arce-Sillas A., Alvarez-Luquin D., Tamayo-Dominguez B., et al. Regulatory T Cells: Molecular Action on Effector Cells in Immune Regulation. Journal of Immunology Research. 2016
3 Corthay A. How do Regulatory T cells Work. Scandinavian Journal of Immunology. 2009, 70: 3260336.
Dear All
What is FOXP3 and what its role and relation to Treg?
the forkheadbox transcription factor Foxp3 is newsepcific marker of treg cells was dicover in 2003 and found that its expression very important and necssary due to thier suppressive activity , in animal study on scurfy mice which lack the expresion of FOXP3 would develop sever lymphoprolerative autoimmune disease , and in human studies found mutaion in the FOXP3 gene can lead to autiimmune disorders
It is a transcription factor localized intracellularly and its most reliable marker for Treg cells. It is mostly restricted to CD4 T cells, but some CD8 express it.it essential for T-cell function and its defects lead to fatal immune dysregulation.it is essential for the maintenance of a developmentally established suppressive program in mature Treg in the periphery.
Foxp3 is a specific marker of Treg cells which its expression is necessary for Treg suppressive activity. It was found that mutation of Foxp3 gene in human can cause autoimmune disease.
it is transcription factor needed for Treg activation and function
Foxp3 is a transcription factor, considered to be most reliable marker of Treg cells. It has an important role in function of Treg. Mutation in FoxP3 gene causes lymphoproliferative disorders and autoimmune diseases due to poor suppressor function.
Reference:
Corthay A. How do regulatory T cells work? Scand J Immunol 2009;70:326-336.
FOXp3 (Forkhead/ winged helix transcription factor box P3) is a transcription factor acting as a marker for Treg. Treg can be classified on the basis of FoxP3 :
a) Resting Treg: CD45RA+ FoxP3 high
b) Activated Treg: CD45RA- FoxP3 high
c) Non suppressive Treg: CD45RA- FoxP3 low
Role of FOXP3 in Treg:
FOXP3 is required in signaling mechanisms of Treg leading to increased expression of Tregs. Also, it stabilizes the phenotype of Tregs.
Reference:
Schmidt JV, Han JM, Macdonald KG, et al. The role of FOXP3 in regulating immune responses. Int Rev Immunol 2014;33:110-128.
FOXP3 is a transcription factor that was discovered at 2003 as a specific marker for Tregs and it’s expression is necessary for their immune suppressive function.
What is FOXP3 and what its role and relation to Treg?
It is an intracellular transcription molecules which is present in large amount in T reg and is important for the development and function of them.1 it can be found also in CD8+cells. T reg can lose it and eventually lose its suppressant effect2
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.
Foxp3 is transcription factor express by Treg CD4 lymphocytes so it is marker and way of monitor their activity
What is Treg and how it is activated?
What is the proposed mechanism(s) of induction of tolerance by Treg?
How would you implement Treg monitoring in clinical transplantation
1. In a study addressing the relation between graft rejection in liver transplant patients and the Tregs/Th17 ratio which was determined by FCM it was found that Lower ratio was found in recipients with graft rejection.
2. Phase 1 clinical trials demonstrate safety and effectiveness of transfusion of adopted Treg in the treatment of DM1 and in BM, liver and kidney transplantation (4, 5, 6, 7) with superiority of antigen(donor)specific over polyclonal Treg (8)
3. Several studies demonstrated safety and efficacy of manipulation of CD4+ T conv cells to express FOXP3 in hemophilia and type 1 DM, rheumatoid arthritis (9, 10, 11)
4. Transducing Treg with chimeric antigen receptors (CAR)
REFERANCES
1. Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S, et al. Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol. (2013) 14:307–8.
2. Lyon MF, Peters J, Glenister PH, Ball S, Wright E. The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles wiskott-aldrich syndrome. Proc Natl Acad Sci USA. (1990) 87:2433–7.
3. Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H. Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol. (2005) 6:1219–27.
4. Trzonkowski P, Dukat-Mazurek A, Bieniaszewska M, Marek-Trzonkowska N, Dobyszuk A, Juscinska J, et al. Treatment of graft-versus-host disease with naturally occurring T regulatory cells. Biodrugs. (2013) 27:605–14.
5. Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, Grabowska M, Derkowska I, Juscinska J, et al. Therapy of type 1 diabetes with CD4(+)CD25(high)CD127-regulatory T cells prolongs survival of pancreatic islets – results of one year follow-up. Clin Immunol. (2014) 153:23–30.
6. Todo S, Yamashita K, Goto R, Zaitsu M, Nagatsu A, Oura T, et al. A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation. Hepatology. (2016) 64:632–43.
7. Sanchez-Fueyo A, Whitehouse G, Grageda N, Cramp ME, Lim TY, Romano M, et al. Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation. Am J Transplant. (2019) 20:1125–36.
8. Romano M, Fanelli G, Albany CJ, Giganti G, Lombardi G. Past, present, and future of regulatory T cell therapy in transplantation and autoimmunity. Front Immunol. (2019) 10:43.
9. Herzog RW, Kuteyeva V, Saboungi R, Terhorst C, Biswas M. Reprogrammed CD4(+) T cells that express FoxP3(+) control inhibitory antibody formation in hemophilia A mice. Front Immunol. (2019) 10:274
10. Jaeckel E, von Boehmer H, Manns MP. Antigen-specific FoxP3-transduced T-cells can control established type 1 diabetes. Diabetes. (2005) 54:306–10.
11. Beavis PA, Gregory B, Green P, Cribbs AP, Kennedy A, Amjadi P, et al. Resistance to regulatory T cell-mediated suppression in rheumatoid arthritis can be bypassed by ectopic foxp3 expression in pathogenic synovial T cells. Proc Natl Acad Sci USA. (2011) 108:16717–22.
Well done
Regulatory T cells are naturally occurring immune modulatory cells, constitute diverse of cells, many Tregs originate from thymus, others arise in periphery from naïve CD4+ T cells on suboptimal exposure to antigens. (1)
The best characterized are CD4+ cells that express high level of IL-2 receptor alpha chain CD25 with transcription factor Foxp3. (2) CD4+ CD25+Foxp3+ natural Tregs play a role in suppression of self reactive cells and are associated with better graft survival. (3)
proposed mechanisms of induction of tolerance:
Treg prevent initiation of unwanted immune activation and suppress ogoing immune response to limit tissue destruction (4)
A study showed that Treg infiltrating the transplanted kidney may have a role in promoting healing by inhibition of inflamatory cytokines produced by other T cells. (5)
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 (6)
Metabolic interference:
Treg express high levels of CD25 which depletes IL-2 that is important for survival & function of T cells. (7)
Inhibitory cytokine release:
Treg release immune suppressive cytokines (IL-10, IL-35) that prevent T cell proliferation and APC maturation. (8)
Cytolysis:
Treg secrete granzymes and perforins which cause apoptosis (9)
Targeting APC:
Treg express CTLA-4 which blocks binding of APC to CD28 causing decreased T cell activation. (10)
Recent studies showed that Treg derived exosomes inhibit T cell proliferation in vitro. (11)
Monitoring the effect of Treg:
The aim of using Treg in transplantation is to decrease immunosuppression protocols, It is important to assure effective expansion of Treg, monitor their long term stability, decrease the risk of nonspecific immunosuppression related to cancer. (12)
Number of Treg in kidney transplant patients with solid tumor was higher than patients without tumors. (13) It is important to develop screening program to exclude presence of tumors before starting infusion of Treg. (11)
A study labelled expanded Treg to monitor the transferred cells by flowcytometry (14)
protocol kidney biopsies, monitoring DSA may be necessary (15)
(1) Panduro, M., Benoist, C. & Mathis, D. Tissue Tregs. Annu. Rev. Immunol. 34, 609–633 (2016)
(2) Martin-Moreno, P.L., Tripathi, S. and Chandraker, A., 2018. Regulatory T cells and kidney transplantation. Clinical Journal of the American Society of Nephrology, 13(11), pp.1760-1764.
(3) L. Ma, H. Zhang, K. Hu, G. Lv, Y. Fu, D.A. Ayana, P. Zhao, Y. Jiang, The imbalance between Tregs, Th17 cells and inflammatory cytokines among renal transplant recipients, BMC Immunol. 16 (1) (2015) 56.
(4) Tang Q, Bluestone JA. The Foxp3 + regulatory T cell: A jack of all trades, master of regulation. Nat Immunol 2008; 9: 239–244
(5) . GandolfoMT,Jang HR, Bagnasco SM, Ko GJ,Agreda P, Satpute SR, Crow MT, King LS, Rabb H: Foxp31 regulatory T cells participate in repair of ischemic acute kidney injury. Kidney Int 76: 717–729, 2009
(6) 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.
(7) akaguchi S, Sakaguchi N, Asano M, ItohM, Toda M. Immunologic self-tolerancemaintained by activated T cells expressingIL-2 receptor alpha-chains (CD25).Breakdown of a single mechanism of self-tolerance causes various autoimmunediseases. J Immunol 1995; 155: 115.
(8) Sawant D, Hamilton K, Vignali D.Interleukin-35: expanding its job profile.J Interfe ron Cytokine Res 2015; 35: 499.
(9) Vignali D, Collison L, Workman C.How regulatory T cells work. Nat RevImmunol 2008; 8: 523.
(10) Qureshi OS, Zheng Y, Nakamura K,et al. Trans-endocytosis of CD80 andCD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science2011; 332: 600.
(11) Smyth LA, Ratnasothy K, Tsang JY, et al.CD73 expression on extracellular vesiclesderived from CD4+ CD25+ Foxp3+ Tcells contributes to their regulatoryfunction. Eur J Immunol 2013; 43: 2430.
(12) Martin-Moreno, P.L., Tripathi, S. and Chandraker, A., 2018. Regulatory T cells and kidney transplantation. Clinical Journal of the American Society of Nephrology, 13(11), pp.1760-1764.
(13) Hope CM, Grace BS, Pilkington KR et al (2014) The immune
phenotype may relate to cancer development in kidney transplant
recipients. Kidney Int 86:175–183
(14) Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, Herold KC, Lares A, Lee MR, Li K, LiuW, Long SA, Masiello LM, Nguyen V, Putnam AL, Rieck M, Sayre PH, Tang Q: Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med 7: 315ra189, 2015
(15) Chandran S, Tang Q, Sarwal M, Laszik ZG, Putnam AL, Lee K, Leung J, Nguyen V, Sigdel T, Tavares EC, Yang JYC, Hellerstein M, Fitch M, Bluestone JA, Vincenti F: Polyclonal regulatory T cell therapy for control of inflammation in kidney transplants. Am J Transplant 17: 2945–2954, 2017
Well done
CD4+ T lymphocytes differentiate into 4 subclasses of T helpers and one regulatory subpopulation (T- reg), while CD8+ differentiate into cytotoxic T cell TCL.
Tregs are a specialized subpopulation of T cells that act to suppress immune response, thereby maintaining homeostasis and self-tolerance. Tregs produced by a normal thymus are called natural, while those formed by differentiation of naive T cells outside the thymus (the periphery) are termed adaptive.
Natural Treg are characterised as expressing both the CD4 T cell co-receptor and CD25, which is a component of the IL-2 receptor. Treg are thus CD4+ CD25+. Expression of the nuclear transcription factor Forkhead box P3 (FoxP3), which is localized intracellulary, is the defining property which determines natural Treg development and function. Additional markers of natural Tregs are CD152 (CTLA-4) and GITR (glucocorticoid-induced TNF receptor). Tregs can be usually identified by flow cytometry.
-Tregs suppress activation, proliferation and cytokine production of CD4+ T cells and CD8+ T cells, NK cells, and Antigen Presenting Cells (APCs), are thought to suppress B cells and T cells and thereby maintain the critical balance between self tolerance and autoimmunity.
-Tregs exert their functions through modulation of APC functions, production of immunoregulatory cytokines such as IL-10, TGF-β, and IL-35, which can contribute to Teff cell suppression. Tregs express coinhibitory receptors like CTLA4 and TIGIT which can also explain their immune inhibitory effect.
Dysregulation in Treg cell frequency or functions may lead to the development of autoimmune disease. Therapeutical Treg modulation is considered to be a promising approach in preventing allograft rejection.
The clinical application of T reg in kidney are related to the objective of achieving tolerance while maintaining tissue repair and managing acute rejection.
A recent study has shown that inducible Treg treatment in a murine model decreased serum donor-specific antibody levels and deposition of IgG within allografts, indicating a potential use in the treatment of humoral rejection.
With regards to the number of Tregs necessary to achieve tolerance, more important than the total dose administered may be increase Tregs to at least 30% of T effectors.
Effect of immunosuppressive drugs on T reg:
-Drugs that alter T reg viability in terms of effect reduction : CNI, MMF, IL2, ATG, B7:CD28 inhibitor
-Drugs that can cause generation/expansion of Treg: mTORi, Alemtezumab, Metformin, Erythropoetin
-Glucocorticoids appear not to affect Tregs
References:
DOI: 10.14712/18059694.2016.63
DOI: 10.1016/j.cellimm.2018.09.008
DOI: 10.2215/CJN.01750218
Excellent Mohamed
I can see your effort. Keep going.
Normal immune system produces subsets of specialized T cells, called regulatory T cells (Tregs) that are specific for immune suppression. Disruption in the development or function of Tregs is a primary cause of autoimmune, allergic, and inflammatory diseases in humans and animals.
the normal thymus produces functionally mature Tregs; mature Tregs persist in the peripheral lymphoid tissue .Treg deficiency in the periphery can lead to chronic T cell-mediated autoimmunity and immunopathology.
Tregs inhibit or regulate function of other immune cells like can promote the down regulation of dendritic cell CD80 and CD86 by a CTLA-4-dependent mechanism. other specialized Tregs may further differentiate to kill or inactivate responder T cells by secreting granzyme/perforin or cytokines (like IL-10).
Treg cells can be generated either in vivo or ex vivo and open hope for new therapies by induce and maintain tolerance .
1-Regulatory T cells and immune toleranceShimon Sakaguchi 1 , Tomoyuki Yamaguchi, Takashi Nomura, Masahiro Ono.
2- Regulatory T cella in transplantation tolerance
kathyrin J.Wood &Shimon Sakaguchi, Nature review immunology 3,199-210, 2003 .
Thanks Saja
Treg cells, subsets of T cells inhibit or regulate function of other immune cells so inhibit immune response to self and non-self antigens so prevent autoimmune diseases. It comes from differentiation of naiive Tcells outside thymus (periphery), and responsible for maintenance of peripheral tolerance, and has anti-tumor function.
Treg are CD4+CD25+, they express nuclear transcription factor FoxP3 which is responsible for its regulatory inhibitory function of Treg and can be used as a marker to monitor Treg post transplant.
Treg cells were activated by :
1- IL-2 lead to its clonal expansion and increased its number.
2- CD28 costimulation will lead to IL-2 secretion which increase Treg numbers.
Mechanism of Treg cells in inducing immune tolerance:
1- Release of inhibitory cytokines like IL-10, TGF-β and IL-35.
2- Treg cells mediate cell lysis by certain mediators like granzyme A and B , and perforin.
3- Apoptosis mediated by cytokine deprived state as Treg cells consume IL-2.
4- Modulate dendritic cell maturation or function; cytotoxic T lymphocyte antigen 4 (CTLA-4) interacts with CD-80/CD-86 and produce inhibitory pro apoptotic molecules.
Dario A. A. Vignali, Lauren W. Collison, Creg J. Workman. How regulatory T cells work. Nature Reviews Immunology 2008, volume 8, pages523–532.
SIMON READ, FIONA POWRIE, Regulatory T Cells. Handbook of clinical neurology. 2014.
Tregs are CD4+ cells that express high level of CD25 along with transcription factor FOXP3. the use of these cells in transplantation is to induce immune tolerance, reduction of immunosuppression, maintaining tissue repair & managing rejection.1
These CD4+,CD25+ Tregs constitute 5%- 10% of peripheral T cells.2
In 1995 small proportion of CD4+,CD25+ was described and their relationship to autoimmune disease was identified.3
In 2003 FOXP3 was discovered.
In recent years preclinical studies shows how the transfer of Tregs prevents GVHD & allograft rejection.
In 2009, the first clinical trial for using Tregs was published
Multiple subpopulations of Tregs were distinguished by the expression of different surface markers, mechanism of activation and how they function.
Tregs can be divided into:
I. naive/ resting cells expressing CD45RA+FOXP3low.
II. effector Tregs expressing CD45RA-FOXP3high.
III. cytokine-producing Tregs expressing CD45RA-FOXP3low.3
Tregs enhance healing of the injured kidney tissue during ischemia reperfusion probably by negative modulation of proinflammatory cytokines.
In acute rejection , recipient derived T cells contribute to graft tolerance if they acquire a resting tissue resident phenotype. A study showed that inducible Treg treatment in a murine model decrease DSA level and IgG deposition within the allograft indicating a potential role in the treatment of ABMR.
It can not be assumed that tolerance induced by Tregs is stable, so monitoring is required, some studies suggested to monitor the infused cells with flow cytometry, however, performing protocol biopsies after Tregs infusion to assess changes in inflammation and monitoring DSA may be necessary.1
References:
Treg cells are a subset of thymus derived CD4+ T cells expressing high levels of IL-2Rα (CD25). Tregs play a crucial role in maintaining immune homeostasis and preventing autoimmunity. CD25 and (FOXP3) is not sufficient for characterizing human Tregs, since effector T cells can upregulate these markers after activation. However methylation status of (TSDR) , a conserved non-coding element within the FoxP3 gene locus, can be used for the identification of the “real” human Tregs. The thymus is the crucial organ for the generation of Tregs. CD4 single positive (SP) cells , following a TCR signal of high strength undergo negative selection, whereas those receiving TCR signals of intermediate strength are able to escape deletion and are committed to differentiate into Tregs. In addition to tTreg, naïve FOXP3−CD4+ T cells can differentiate in the periphery to become FOXP3+cells, which are known as induced Tregs (iTregs) or peripheral Tregs (pTregs). The generation of iTregs is likely promoted by non-self-antigens (allergens, food, microbiota. . iTregs controls immune responses to commensal antigens and prevent allergic type reactions.
The mechanisms used by Tregs to suppress different immune cells can either be considered direct whereby Tregs themselves elicit a direct response on a target cell, or indirect, in which a third-party cell or molecule is affected and in turn suppresses the target cell .
Direct mechanisms include the secretion of cytokines such as IL-10, TGFβ and IL-35 and the production of granzyme and perforin, enzymes leading to apoptosis in target cells .
Indirect mechanisms include the expression of CD39/CD73, which deplete the microenvironment of extracellular ATP via the generation of adenosine and AMP, molecules with immunosuppressive effects.
T regs thus suppress T cells, B cells, monocytes, dentritic cells, granulocytes and innate immune cells.
clinical studies have shown the safety and feasibility of Tregs infusion in preventing graft rejection. Immunosuppressive drugs like tacrolimus, mycophenolate and methylprednisolone reduced Tregs’ viability and proliferation in a dose dependent manner. Different strategies are now under investigation with the aim to tailor the immunosuppressive regimen to the Tregs or find the best timing for their infusion. Treg localization and migration is the the main challenge.
Ongoing clinical trials will be crucial to better understand the tolerated Treg dose, timing of infusion and the immunosuppressive regimen to preserve/favor them. Best strategy is represented by the combined therapy whereby antigen-specific Treg will be infused together with either low dose of IL2, rapamycin or in the future TNFR2 agonists.
Thank you for mentioning the effects of Tregs in IRI, acute rejection.
Absolutely right, the tolerance induced by Tregs is stable, and this is one of the limitations of the studies using them.
Thankyou Hoda now you mentioned roles played by Tregs in
IRI
Acute rejection
ABMR
could there be a role in chronic rejection
And is there a relation between degree of HLA mismatch and role of Tregs.