Abstract
Regulatory T cells are now recognized as important mediators of self-tolerance and may mediate responses to immune therapy. The mechanisms of action of these cells are diverse, and some studies suggest that there may be defects in regulatory cells in patients with type 1 diabetes. These cells may be expanded by immune therapy, suggesting the possible development of adoptive immune therapy to transfer regulation with the cells.
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References and Recommended Reading
Danke NA, Koelle DM, Yee C, et al.: Autoreactive T cells in healthy individuals. J Immunol 2004, 172:5967–5972.
Fowell D, Mason D: Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential. J Exp Med 1993, 177:627–636.
Thornton AM, Shevach EM: CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 1998, 188:287–296.
Sakaguchi S, Sakaguchi N, Asano M, et al.: Immunologic selftolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995, 155:1151–1164.
Lepault F, Gagnerault MC: Characterization of peripheral regulatory CD4+ T cells that prevent diabetes onset in nonobese diabetic mice. J Immunol 2000, 164:240–247. Described naturally occurring regulatory T cells that can inhibit diabetes in the NOD mouse.
You S, Slehoffer G, Barriot S, et al.: Unique role of CD4+CD62L+ regulatory T cells in the control of autoimmune diabetes in T cell receptor transgenic mice. Proc Natl Acad Sci U S A 2004, 101(suppl 2):14580–14585.
Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA: CD4+CD25high regulatory cells in human peripheral blood. J Immunol 2001, 167:1245–1253. Illustrated CD4+CD25 regulatory T cells in humans that are analogous to those originally identified in mice.
McHugh RS, Whitters MJ, Piccirillo CA, et al.: CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002, 16:311–323.
Shimizu J, Yamazaki S, Takahashi T, et al.: Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 2002, 3:135–142.
Huang CT, Workman CJ, Flies D, et al.: Role of LAG-3 in regulatory T cells. Immunity 2004, 21:503–513.
Sakaguchi S: The origin of FOXP3-expressing CD4+ regulatory T cells: thymus or periphery. J Clin Invest 2003, 112:1310–1312.
Ramsdell F: Foxp3 and natural regulatory T cells: key to a cell lineage? Immunity 2003, 19:165–168.
Bennett CL, Christie J, Ramsdell F, et al.: The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001, 27:20–21.
Wildin RS, Ramsdell F, Peake J, et al.: X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 2001, 27:18–20.
Brunkow ME, Jeffery EW, Hjerrild KA, et al.: Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 2001, 27:68–73.
Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science 2003, 299:1057–1061.
Khattri R, Cox T, Yasayko SA, Ramsdell F: An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 2003, 4:337–342.
Stephens LA, Mason D: CD25 is a marker for CD4+ thymocytes that prevent autoimmune diabetes in rats, but peripheral T cells with this function are found in both CD25+ and CD25-subpopulations. J Immunol 2000, 165:3105–3110.
Levings MK, Sangregorio R, Galbiati F, et al.: IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol 2001, 166:5530–5539.
Cobbold SP, Nolan KF, Graca L, et al.: Regulatory T cells and dendritic cells in transplantation tolerance: molecular markers and mechanisms. Immunol Rev 2003, 196:109–124.
Jiang H, Chess L: The specific regulation of immune responses by CD8+ T cells restricted by the MHC class Ib molecule, Qa-1. Annu Rev Immunol 2000, 18:185–216.
Ware R, Jiang H, Braunstein N, et al.: Human CD8+ T lymphocyte clones specific for T cell receptor V beta families expressed on autologous CD4+ T cells. Immunity 1995, 2:177–184.
Chang CC, Ciubotariu R, Manavalan JS, et al.: Tolerization of dendritic cells by TS cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nat Immunol 2002, 3:237–243.
Suciu-Foca N, Manavalan JS, Cortesini R: Generation and function of antigen-specific suppressor and regulatory T cells. Transpl Immunol 2003, 11:235–244.
Wilson SB, Kent SC, Patton KT, et al.: Extreme Th1 bias of invariant Valpha24JalphaQ T cells in type 1 diabetes. Nature 1998, 391:177–181.
Lehuen A, Lantz O, Beaudoin L, et al.: Overexpression of natural killer T cells protects Valpha14-Jalpha281 transgenic nonobese diabetic mice against diabetes. J Exp Med 1998, 188:1831–1839.
Carnaud C, Gombert J, Donnars O, et al.: Protection against diabetes and improved NK/NKT cell performance in NOD.NK1.1 mice congenic at the NK complex. J Immunol 2001, 166:2404–2411.
Ogasawara K, Hamerman JA, Hsin H, et al.: Impairment of NK cell function by NKG2D modulation in NOD mice. Immunity 2003, 18:41–51.
Li J, Goldstein I, Glickman-Nir E, et al.: Induction of TCR Vbeta-specific CD8+ CTLs by TCR Vbeta-derived peptides bound to HLA-E. J Immunol 2001, 167:3800–3808.
Belghith M, Bluestone JA, Barriot S, et al.: TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat Med 2003, 9:1202–1208. Shows the induction of CD4+CD25+ T cells with anti-CD3 mAb and the TGF-β-dependent mechanism of immune regulation.
Nakamura K, Kitani A, Fuss I, et al.: TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol 2004, 172:834–842.
Green EA, Gorelik L, McGregor CM, et al.: CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGFbeta-TGF-beta receptor interactions in type 1 diabetes. Proc Natl Acad Sci U S A 2003, 100:10878–10883.
Piccirillo CA, Letterio JJ, Thornton AM, et al.: CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness. J Exp Med 2002, 196:237–246.
ShevachEM: Regulatory T cells in autoimmunity*. Annu Rev Immunol 2000, 18:423–449.
Barthlott T, Kassiotis G, Stockinger B: T cell regulation as a side effect of homeostasis and competition. J Exp Med 2003, 197:451–460.
Waldmann H, Qin S, Cobbold S: Monoclonal antibodies as agents to reinduce tolerance in autoimmunity. J Autoimmun 1992, 5 Suppl A:93–102.
Herold KC, Burton JB, Francois F, et al.: Activation of human T cells by FcR nonbinding anti-CD3 mAb, hOKT3gamma1(Ala-Ala). J Clin Invest 2003, 111:409–418. These studies in patients treated with anti-CD3 mAb describe IL-10+CD4+ T cells in vivo.
Tarbell KV, Lee M, Ranheim E, et al.: CD4(+) T cells from glutamic acid decarboxylase (GAD)65-specific T cell receptor transgenic mice are not diabetogenic and can delay diabetes transfer. J Exp Med 2002, 196:481–492.
Kim SK, Tarbell KV, Sanna M, et al.: Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells. Proc Natl Acad Sci U S A 2004, 101:14204–14209.
Martinez NR, Augstein P, Moustakas AK, et al.: Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide. J Clin Invest 2003, 111:1365–1371.
Roncarolo MG, Bacchetta R, Bordignon C, et al.: Type 1 T regulatory cells. Immunol Rev 2001, 182:68–79.
Bluestone JA, Abbas AK: Natural versus adaptive regulatory T cells. Nat Rev Immunol 2003, 3:253–257.
Asano M, Toda M, Sakaguchi N, Sakaguchi S: Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 1996, 184:387–396.
Salomon B, Lenschow DJ, Rhee L, et al.: B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 2000, 12:431–440. Identified the CD28 dependence of development of CD4+CD25+ T cells in the NOD mouse model.
Peng Y, Laouar Y, Li MO, et al.: TGF-beta regulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes. Proc Natl Acad Sci U S A 2004, 101:4572–4577.
Walker MR, Kasprowicz DJ, Gersuk VH, et al.: Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25−T cells. J Clin Invest 2003, 112:1437–1443.
Yagi H, Nomura T, Nakamura K, et al.: Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. Int Immunol 2004, 16:1643–1656.
Hering BJ, Kandaswamy R, Harmon JV, et al.: Transplantation of cultured islets from two-layer preserved pancreases in type 1 diabetes with anti-CD3 antibody. Am J Transplant 2004, 4:390–401.
Asseman C, Powrie F: Interleukin 10 is a growth factor for a population of regulatory T cells. Gut 1998, 42:157–158.
Asseman C, Mauze S, Leach MW, et al.: An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 1999, 190:995–1004.
Harrison LC, Solly NR, Martinez NR: (Pro)insulin-specific regulatory T cells. Novartis Found Symp 2003, 252:132–141;discussion 141–135, 203–110.
Tang Q, Henriksen KJ, Bi M, et al.: In vitro-expanded antigenspecific regulatory T cells suppress autoimmune diabetes. J Exp Med 2004, 199:1455–1465. Suggested an approach to the expansion of antigen-specific regulatory T cells.
Apostolou I, Sarukhan A, Klein L, von Boehmer H: Origin of regulatory T cells with known specificity for antigen. Nat Immunol 2002, 3:756–763.
Stockinger B, Barthlott T, Kassiotis G: T cell regulation: a special job or everyone's responsibility? Nat Immunol 2001, 2:757–758.
Mueller R, Bradley LM, Krahl T, Sarvetnick N: Mechanism underlying counterregulation of autoimmune diabetes by IL-4. Immunity 1997, 7:411–418.
Kukreja A, Cost G, Marker J, et al.: Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest 2002, 109:131–140.
Lee PT, Putnam A, Benlagha K, et al.: Testing the NKT cell hypothesis of human IDDM pathogenesis. J Clin Invest 2002, 110:793–800.
Arif S, Tree TI, Astill TP, et al.: Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J Clin Invest 2004, 113:451–463.
Herold KC: Achieving antigen-specific immune regulation. J Clin Invest 2004, 113:346–349.
Homann D, Holz A, Bot A, et al.: Autoreactive CD4+ T cells protect from autoimmune diabetes via bystander suppression using the IL-4/Stat6 pathway. Immunity 1999, 11:463–472.
Takahashi K, Honeyman MC, Harrison LC: Impaired yield, phenotype, and function of monocyte-derived dendritic cells in humans at risk for insulin-dependent diabetes. J Immunol 1998, 161:2629–2635.
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Bisikirska, B.C., Herold, K.C. Regulatory T cells and type 1 diabetes. Curr Diab Rep 5, 104–109 (2005). https://doi.org/10.1007/s11892-005-0036-x
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DOI: https://doi.org/10.1007/s11892-005-0036-x