Regulatory T cell
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The regulatory T cells (Tregs), formerly known as suppressor T cells, are a subpopulation of T cells which modulate the immune system, maintain tolerance to self-antigens, and abrogate autoimmune disease. These cells generally suppress or downregulate induction and proliferation of effector T cells. Additional regulatory T cells known as Treg17 cells have recently been identified. Mouse models have suggested that modulation of Tregs can treat autoimmune disease and cancer, and facilitate organ transplantation.
Regulatory T cell populations
T regulatory cells are a component of the immune system that suppress immune responses of other cells. This is an important "self-check" built into the immune system to prevent excessive reactions. Regulatory T cells come in many forms with the most well-understood being those that express CD4, CD25, and Foxp3 (CD4+CD25+ regulatory T cells). These "Tregs" are different from helper T cells. Another regulatory T cell subset is Treg17 cells. Regulatory T cells are involved in shutting down immune responses after they have successfully eliminated invading organisms, and also in preventing autoimmunity cells.
CD4+ Foxp3+ regulatory T cells have been called "naturally-occurring" regulatory T cells to distinguish them from "suppressor" T cell populations that are generated in vitro. Additional regulatory T cell populations include Tr1, Th3, CD8+CD28-, and Qa-1 restricted T cells. The contribution of these populations to self-tolerance and immune homeostasis is less well defined. FOXP3 can be used as a good marker for mouse CD4+CD25+ T cells, although recent studies have also shown evidence for FOXP3 expression in CD4+CD25- T cells. In humans, FoxP3 is also expressed by recently activated conventional T-cells and thus does not specifically identify human T-reg.
All T cells come from progenitor cells from the bone marrow, which become committed to their lineage in the thymus. All T cells begin as CD4-CD8-TCR- cells at the DN (double-negative) stage, where an individual cell will rearrange its T cell receptor genes to form a unique, functional molecule, which they, in turn, test against cells in the thymic cortex for a minimal level of interaction with self-MHC. If they receive these signals, they proliferate and express both CD4 and CD8, becoming double-positive cells. The selection of Tregs occurs on radio-resistant haemopoietically-derived MHC class II-expressing cells in the medulla or Hassal’s corpuscles in the thymus. At the DP (double-positive) stage, they are selected by their interaction with the cells within the thymus, begin the transcription of Foxp3, and become Treg cells, although they may not begin to express Foxp3 until the single-positive stage, at which point they are functional Tregs. Treg do not have the limited TCR expression of NKT or γδ T cells; Treg have a larger TCR diversity than effector T cells, biased towards self-peptides.
The process of Treg selection is determined by the affinity of interaction with the self-peptide MHC complex. Selection to become a Treg is a “Goldilocks” process; T cell that receives very strong signals will undergo apoptotic death; a cell that receives a weak signal will survive and be selected to become an effector cell. If a T cell receives an intermediate signal, then it will become a regulatory cell. Due to the stochastic nature of the process of T cell activation, all T cell populations with a given TCR will end up with a mixture of Teff and Treg – the relative proportions determined by the affinities of the T cell for the self-peptide-MHC. Even in mouse models with TCR-transgenic cells selected on specific-antigen-secreting stroma, deletion or conversion is not complete.
Foxp3+ Treg generation in the thymus is delayed by several days compared to Teff cells and does not reach adult levels in either the thymus or periphery until around three weeks post-partum. Treg cells require CD28 co-stimulation and B7.2 expression is largely restricted to the medulla, the development of which seems to parallel the development of Foxp3+ cells. It has been suggested that the two are linked, but no definitive link between the processes has yet been shown. TGF-β is not required for Treg functionality, in the thymus, as thymic Treg from TGF-β insensitive TGFβRII-DN mice are functional.
The immune system must be able to discriminate between self and non-self. When self/non-self discrimination fails, the immune system destroys cells and tissues of the body and as a result causes autoimmune diseases. Regulatory T cells actively suppress activation of the immune system and prevent pathological self-reactivity, i.e. autoimmune disease. The critical role regulatory T cells play within the immune system is evidenced by the severe autoimmune syndrome that results from a genetic deficiency in regulatory T cells (IPEX syndrome - see also below).
The molecular mechanism by which regulatory T cells exert their suppressor/regulatory activity has not been definitively characterized and is the subject of intense research. In vitro experiments have given mixed results regarding the requirement of cell-to-cell contact with the cell being suppressed. The immunosuppressive cytokines TGF-beta and Interleukin 10 (IL-10) have also been implicated in regulatory T cell function.
Induced regulatory T cells
Induced Regulatory T (iTreg) cells (CD4+ CD25+ Foxp3+) are suppressive cells involved in tolerance. iTreg cells have been shown to suppress T cell proliferation and experimental autoimmune diseases. These cells include Treg17 cells. iTreg cells develop from mature CD4+ conventional T cells outside of the thymus: a defining distinction between natural regulatory T (nTreg) cells and iTreg cells. Though iTreg and nTreg cells share a similar function iTreg cells have recently been shown to be "an essential non-redundant regulatory subset that supplements nTreg cells, in part by expanding TCR diversity within regulatory responses". Acute depletion of the iTreg cell pool in mouse models has resulted in inflammation and weight loss. The contribution of nTreg cells versus iTreg cells in maintaining tolerance is unknown, but both are important. Epigenetic differences have been observed between nTreg and iTreg cells, with the former having more stable Foxp3 expression and wider demethylation.
Regulatory T cells and disease
An important question in the field of immunology is how the immunosuppressive activity of regulatory T cells is modulated during the course of an ongoing immune response. While the immunosuppressive function of regulatory T cells prevents the development of autoimmune disease, it is not desirable during immune responses to infectious microorganisms. Current hypotheses suggest that, upon encounter with infectious microorganisms, the activity of regulatory T cells may be downregulated, either directly or indirectly, by other cells to facilitate elimination of the infection. Experimental evidence from mouse models suggests that some pathogens may have evolved to manipulate regulatory T cells to immunosuppress the host and so potentiate their own survival. For example, regulatory T cell activity has been reported to increase in several infectious contexts, such as retroviral infections (the most well-known of which is HIV), mycobacterial infections (like tuberculosis), and various parasitic infections including Leishmania and malaria.
Studies of human subjects with a history of leishmania infection suggest that modulation of CD8+ suppressor T cells is, at least partly, mediated by cytokines. Leishmania specific CD4+ helper T cells predominate in adults with strong protective immunity (skin-test positive with no history of clinical infection). When added to autologous leishmania infected macrophages these T cells cause parasite death and secretion of large amounts of interferon-gamma and lymphotoxin. CD8+ T suppressor cells predominate in patients with no protective immunity (visceral leishmaniasis patients). When added to autologous peripheral blood mononuclear cells isolated after successful treatment, these T cells inhibit interferon-gamma secretion and proliferation and increase interleukin-6 and interleukin-10 secretion. A soluble factor(s) generated by antigen or phytohemagglutinin stimulation of leishmania-specific CD4+ helper T cells from skin-test positive adults killed CD8+ T cells but not CD4+ helper T cells when added to culture media. Soluble factors generated by antigen stimulation of peripheral blood mononuclear cells from skin-test positive adults prevented CD8+ suppressor T cell mediated increases in interleukin-10 secretion. These findings suggest that antigen stimulation of CD4+ helper T cells results in production of cytokines that kill or down regulate CD8+ T suppressor cells. Once the leishmania infection has been eliminated and leishmania antigens are gone, CD8+ T suppressor cells down-regulate CD4+ T helper cells. Isolation of cytokines that inhibit and kill CD8+ T suppressor cells might be useful in treating diseases that involve immune suppression such as leishmaniasis, AIDS, and certain cancers.
CD4+ Regulatory T cells are often associated with solid tumours in both humans and murine models. Increased numbers of regulatory T cells in breast, colorectal and ovarian cancers is associated with a poorer prognosis.
CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25− T cells.
Similar to other T cells, regulatory T cells develop in the thymus. The latest research suggests that regulatory T cells are defined by expression of the forkhead family transcription factor FOXP3 (forkhead box p3). Expression of FOXP3 is required for regulatory T cell development and appears to control a genetic program specifying this cell's fate. The large majority of Foxp3-expressing regulatory T cells are found within the major histocompatibility complex (MHC) class II restricted CD4-expressing (CD4+) population and express high levels of the interleukin-2 receptor alpha chain (CD25). In addition to the Foxp3-expressing CD4+ CD25+, there also appears to be a minor population of MHC class I restricted CD8+ Foxp3-expressing regulatory T cells. These Foxp3-expressing CD8+ T cells do not appear to be functional in healthy individuals but are induced in autoimmune disease states by T cell receptor stimulation to suppress IL-17-mediated immune responses. Unlike conventional T cells, regulatory T cells do not produce IL-2 and are therefore anergic at baseline.
A number of different methods are employed in research to identify and monitor Treg cells. Originally, high expression of CD25 and CD4 surface markers was used (CD4+CD25+ cells). This is problematic as CD25 is also expressed on non-regulatory T cells in the setting of immune activation such as during an immune response to a pathogen. As defined by CD4 and CD25 expression, regulatory T cells comprise about 5-10% of the mature CD4+ T cell subpopulation in mice and humans, while about 1-2% of Treg can be measured in whole blood. The additional measurement of cellular expression of Foxp3 protein allowed a more specific analysis of Treg cells (CD4+CD25+Foxp3+ cells). However, Foxp3 is also transiently expressed in activated human effector T cells, thus complicating a correct Treg analysis using CD4, CD25 and Foxp3 as markers in humans. Therefore, some research groups use another marker, the absence or low-level expression of the surface protein CD127 in combination with the presence of CD4 and CD25. Several additional markers have been described, e.g., high levels of CTLA-4 (cytotoxic T-lymphocyte associated molecule-4) and GITR (glucocorticoid-induced TNF receptor) are also expressed on regulatory T cells, however the functional significance of this expression remains to be defined. There is a great interest in identifying cell surface markers that are uniquely and specifically expressed on all Foxp3-expressing regulatory T cells. However, to date no such molecule has been identified.
In addition to the search for novel protein markers, a different method to analyze and monitor Treg cells more accurately has been described in the literature. This method is based on DNA methylation analysis. Only in Treg cells, but not in any other cell type, including activated effector T cells, a certain region within the foxp3 gene (TSDR, Treg-specific-demethylated region) is found demethylated, which allows to monitor Treg cells through a PCR reaction or other DNA-based analysis methods. Interplay between the Th17 cells and regulatory T cells are importnant in many diseases like respiratory diseases.
Tregitopes, or regulatory T cell epitopes, were discovered in 2008 and consist of linear sequences of amino acids contained within monoclonal antibodies and immunoglobulin G (IgG). Since their discovery, evidence has indicated Tregitopes may be crucial to the activation of natural regulatory T cells. Potential applications of Tregitopes have been hypothesized: tolerization to transplants, protein drugs, blood transfer therapies, and type I diabetes as well as reduction of immune response for the treatment of allergies.
Genetic mutations in the gene encoding Foxp3 have been identified in both humans and mice based on the heritable disease caused by these mutations. This disease provides the most striking evidence that regulatory T cells play a critical role in maintaining normal immune system function. Humans with mutations in Foxp3 suffer from a severe and rapidly fatal autoimmune disorder known as Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome.
The IPEX syndrome is characterized by the development of overwhelming systemic autoimmunity in the first year of life, resulting in the commonly observed triad of watery diarrhea, eczematous dermatitis, and endocrinopathy seen most commonly as insulin-dependent diabetes mellitus. Most individuals have other autoimmune phenomena including Coombs-positive hemolytic anemia, autoimmune thrombocytopenia, autoimmune neutropenia, and tubular nephropathy. The majority of affected males die within the first year of life of either metabolic derangements or sepsis. An analogous disease is also observed in a spontaneous Foxp3-mutant mouse known as “scurfy”.
- Hori S, Nomura T, Sakaguchi S (2003). "Control of regulatory T cell development by the transcription factor Foxp3". Science 299 (5609): 1057–61. doi:10.1126/science.1079490. PMID 12522256.
- Singh B, Schwartz JA, Sandrock C, Bellemore SM, Nikoopour E (2013). "Modulation of autoimmune diseases by interleukin (IL)-17 producing regulatory T helper (Th17) cells". Indian J Med Res. 138: 591–4. PMID 24434314.
- Shevach EM (2000). "Regulatory T cells in autoimmmunity". Annu Rev Immunol 18: 423–49. doi:10.1146/annurev.immunol.18.1.423. PMID 10837065.
- Sakaguchi S (2004). "Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses". Annu Rev Immunol 22: 531–62. doi:10.1146/annurev.immunol.21.120601.141122. PMID 15032588.
- Haribhai D, Williams JB, Jia S, Nickerson D, Schmitt EG, Edwards B, Ziegelbauer J, Yassai M, Li SH, Relland LM, Wise PM, Chen A, Zheng YQ, Simpson PM, Gorski J, Salzman NH, Hessner MJ, Chatila TA, Williams CB (July 2011). "A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity". Immunity 35 (1): 109–22. doi:10.1016/j.immuni.2011.03.029. PMC 3295638. PMID 21723159.
- Holaday BJ, Pompeu MM, Jeronimo S, Texeira MJ, Sousa Ade A, Vasconcelos AW, Pearson RD, Abrams JS, Locksley RM (December 1993). "Potential role for interleukin-10 in the immunosuppression associated with kala azar". J. Clin. Invest. 92 (6): 2626–32. doi:10.1172/JCI116878. PMC 288459. PMID 8254019.
- Holaday BJ (1999). "Immunotherapy for visceral leishmaniasis: ability of factors produced during anti-leishmania responses of skin test positive adults to inhibit peripheral blood mononuclear cell activities associated with visceral leishmaniasis". Mem. Inst. Oswaldo Cruz 94 (1): 55–66. doi:10.1590/s0074-02761999000100013. PMID 10029912.
- Dranoff G (December 2005). "The therapeutic implications of intratumoral regulatory T cells". Clin. Cancer Res. 11 (23): 8226–9. doi:10.1158/1078-0432.CCR-05-2035. PMID 16322278.
- Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM (October 2007). "CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells". Blood 110 (7): 2537–44. doi:10.1182/blood-2007-03-082578. PMC 1988926. PMID 17615291.
- Marson, Alexander et al. (2009). "Foxp3 occupancy and regulation of key target genes during T-cell stimulation". Nature 445 (?): 931–935. doi:10.1038/nature05478. PMC 3008159. PMID 17237765.
- Ellis SD, McGovern JL, van Maurik A, Howe D, Ehrenstein MR, Notley CA. "Induced CD8+FoxP3+ Treg cells in rheumatoid arthritis are modulated by p38 phosphorylation and monocytes expressing membrane tumor necrosis factor α and CD86.". 2014. Arthritis Rheumatol. 66(10):2694-705. doi: 10.1002/art.38761. PMID 24980778
- Wieczorek G, Asemissen A, Model F, Turbachova I, Floess S, Liebenberg V, Baron U, Stauch D, Kotsch K, Pratschke J, Hamann A, Loddenkemper C, Stein H, Volk HD, Hoffmüller U, Grützkau A, Mustea A, Huehn J, Scheibenbogen C, Olek S (January 2009). "Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue". Cancer Res. 69 (2): 599–608. doi:10.1158/0008-5472.CAN-08-2361. PMID 19147574.
- Agarwal, A; Singh, M; Chatterjee, BP; Chauhan, A; Chakraborti, A (2014). "Interplay of T Helper 17 Cells with CD4(+)CD25(high) FOXP3(+) Tregs in Regulation of Allergic Asthma in Pediatric Patients.". International journal of pediatrics 2014: 636238. doi:10.1155/2014/636238. PMID 24995020.
- Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K, Scott ZA, Coyle AJ, Reed JL, Van Snick J, Strom TB, Zheng XX, Noelle RJ (August 2006). "Mast cells are essential intermediaries in regulatory T-cell tolerance". Nature 442 (7106): 997–1002. doi:10.1038/nature05010. PMID 16921386.
- Tregitopes can dampen unwanted immune responses through selective activation. "Tregitopes". EpiVax, Inc. Retrieved July 2013.
- . Molecular Therapy http://www.nature.com/mt/journal/vaop/naam/abs/mt2013166a.html. Retrieved July 2013. Missing or empty
- (PDF). Blood Journal http://www.epivax.com/wp-content/uploads/2013/02/DeGroot_Tregitope_Blood_2008.pdf. Retrieved July 2013. Missing or empty
- "New $2.25M infusion of NIH funds for EpiVax' Tregitope, proposed "Paradigm-Shifting" Treatment". Fierce Biotech Research. Retrieved July 2013.
- Su Y, Rossi R, De Groot AS, Scott DW (August 2013). "Regulatory T cell epitopes (Tregitopes) in IgG induce tolerance in vivo and lack immunogenicity per se". J. Leukoc. Biol. (Journal of Leukocyte Biology) 94 (2): 377–83. doi:10.1189/jlb.0912441. PMID 23729499.
- Cousens, LP; Su, Y; McClaine, E; Li, X; Terry, F; Smith, R; Lee, J; Martin, W; Scott, DW; De Groot, Anne S. (2013). "Application of IgG-Derived Natural Treg Epitopes (IgG Tregitopes) to Antigen-Specific Tolerance Induction in a Murine Model of Type 1 Diabetes". Journal of Diabetes Research (Journal of Diabetes Research) 2013: 621693. doi:10.1155/2013/621693. PMC 3655598. PMID 23710469.
- (PDF). Human Vaccines & Immunotherapeutics http://www.epivax.com/wp-content/uploads/2013/02/Tregitope_Teaching-Tolerence_Pompe_Disease.pdf. Retrieved July 2013. Missing or empty
- (PDF). Journal of Clinical Immunology http://www.epivax.com/wp-content/uploads/2013/02/Tregitope-Clinical-Immunology-2012.pdf. Retrieved July 2013. Missing or empty
- (PDF). Autoimmunity Reviews http://www.epivax.com/wp-content/uploads/2013/02/Tregitope-update_Autoimmunity-Reviews-2012.pdf. Retrieved July 2013. Missing or empty
- (PDF). World Journal of Gastroenterology http://www.epivax.com/wp-content/uploads/2013/02/Adeno-associated-virus-mediated-delivery-of-Tregitope-167-2012.pdf. Retrieved July 2013. Missing or empty
- (PDF). Neurology Research International http://www.epivax.com/wp-content/uploads/2013/02/Tregitopes_MS_DeGroot_2011.pdf. Retrieved July 2013. Missing or empty
- (PDF). Blood Journal http://www.epivax.com/wp-content/uploads/2013/02/DeGroot_Tregitope_Blood_2008.pdf. Retrieved July 2013. Missing or empty
- Online Mendelian Inheritance in Man IPEX
- ipex at NIH/UW GeneTests