Abstract
Naturally arising CD25+CD4+ regulatory T cells, which express the transcription factor Foxp3, play key roles in themaintenance of immunologic self-tolerance and negative control of a variety of physiological and pathological immune responses. The majority of them are produced by the normal thymus as a functionally mature T cell subpopulation specialized for suppressive function. Their generation is in part genetically and developmentally controlled. Genetically determined or environmentally induced abnormality in CD25+CD4+ regulatory T cell development, maintenance, and function can be a cause of autoimmune disease in humans.
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References
Walker LS, Abbas AK (2002) The enemy within: keeping self-reactive T cells at bay in the periphery. Nat Rev Immunol 2:11–19
Wekerle H, Bradl M, Linington C, Kaab G, Kojima K (1996) The shaping of the brain-specific T lymphocyte repertoire in the thymus. Immunol Rev 149:231–243
Danke NA, Koelle DM, Yee C, Beheray S, Kwok WW(2004) Autoreactive T cells in healthy individuals. J Immunol 172:5967–5972
Sakaguchi S (2000) Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101:455–458
Shevach EM (2000) Regulatory T cells in autoimmmunity. Annu Rev Immunol 18:423–449
Maloy KJ, Powrie F (2001) Regulatory T cells in the control of immune pathology. Nat Immunol 2:816–822
Sakaguchi S (2004) Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531–562
Sakaguchi S, Takahashi T, Nishizuka Y (1982) Study on cellular events in post-thymectomy autoimmune oophoritis in mice. II. Requirement of Lyt-1 cells in normal female mice for the prevention of oophoritis. J Exp Med 156:1577–1586
Penhale WJ, Farmer A, McKenna RP, Irvine WJ (1973) Spontaneous thyroiditis in thymectomized and irradiated Wistar rats. Clin Exp Immunol 15:225–236
Sakaguchi S, Fukuma K, Kuribayashi K, Masuda T (1985) Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J Exp Med 161:72–87
Sugihara S, Izumi Y, Yoshioka T, Yagi H, Tsujimura T, Tarutani O, Kohno Y, Murakami S, Hamaoka T, Fujiwara H (1988) Autoimmune thyroiditis induced in mice depleted of particular T cell subsets. I. Requirement of Lyt-1 dull L3T4 bright normal T cells for the induction of thyroiditis. J Immunol 141:105–113
Smith H, Lou YH, Lacy P, Tung KS (1992) Tolerance mechanism in experimental ovarian and gastric autoimmune diseases. J Immunol 149:2212–2218
Powrie F, Mason D (1990) OX-22high CD4+ T cells induce wasting disease with multiple organ pathology: prevention by the OX-22low subset. J Exp Med 172:1701–1708
McKeever U, Mordes JP, Greiner DL, Appel MC, Rozing J, Handler ES, Rossini AA (1990) Adoptive transfer of autoimmune diabetes and thyroiditis to athymic rats. Proc Natl Acad Sci U S A 87:7618–7622
Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance 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 155:1151–1164
Itoh M, Takahashi T, Sakaguchi N, Kuniyasu Y, Shimizu J, Otsuka F, Sakaguchi S (1999) Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol 162:5317–5326
Kyewski B, Derbinski J (2004) Self-representation in the thymus: an extended view. Nat Rev Immunol 4:688–698
Asano M, Toda M, Sakaguchi N, Sakaguchi S (1996) Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 184:387–396
Godfrey VL, Wilkinson JE, Russell LB (1991) X-linked lymphoreticular disease in the scurfy (sf) mutant mouse. Am J Pathol 138:1379–1387
Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27:68–73
Gambineri E, Torgerson TR, Ochs HD (2003) Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol 15:430–435
Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061
Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336
Khattri R, Cox T, Yasayko SA, Ramsdell F (2003) An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4:337–342
Setoguchi R, Hori S, Takahashi T, Sakaguchi S (2005) Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 201:723–735
Horak I, Lohler J, Ma A, Smith KA (1995) Interleukin-2 deficient mice: a new model to study autoimmunity and self-tolerance. Immunol Rev 148:35–44
Papiernik M, de Moraes ML, Pontoux C, Vasseur F, Penit C (1998) Regulatory CD4 T cells: expression of IL-2R alpha chain, resistance to clonal deletion and IL-2 dependency. Int Immunol 10:371–378
Wolf M, Schimpl A, Hunig T (2001) Control of T cell hyperactivation in IL-2-deficient mice by CD4(+)CD25(-) and CD4(+)CD25(+) T cells: evidence for two distinct regulatory mechanisms. Eur J Immunol 31:1637–1645
Furtado GC, Curotto de Lafaille MA, Kutchukhidze N, Lafaille JJ (2002) Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J Exp Med 196:851–857
Malek TR, Yu A, Vincek V, Scibelli P, Kong L (2002) CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17:167–178
Almeida AR, Legrand N, Papiernik M, Freitas AA (2002) Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. J Immunol 169:4850–4860
Thornton AM, Donovan EE, Piccirillo CA, Shevach EM (2004) Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J Immunol 172:6519–6523
Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12:431–440
Read S, Malmstrom V, Powrie F (2000)Cytotoxic Tlymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 192:295–302
Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S (2000) Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192:303–310
Bachmann MF, Kohler G, Ecabert B, Mak TW, Kopf M (1999) Cutting edge: lymphoproliferative disease in the absence of CTLA-4 is not T cell autonomous. J Immunol 163:1128–1131
Tang Q, Boden EK, Henriksen KJ, Bour-Jordan H, Bi M, Bluestone JA (2004) Distinct roles of CTLA-4 and TGF-beta in CD4+CD25+ regulatory T cell function. Eur J Immunol 34:2996–3005
Kumanogoh A, Wang X, Lee I, Watanabe C, Kamanaka M, Shi W, Yoshida K, Sato T, Habu S, Itoh M, Sakaguchi N, Sakaguchi S, Kikutani H (2001) Increased T cell autoreactivity in the absence of CD40-CD40 ligand interactions: a role of CD40 in regulatory T cell development. J Immunol 166:353–360
Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S (2002) Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological selftolerance. Nat Immunol 3:135–142
Baecher-Allan C, Hafler DA (2004) Suppressor T cells in human diseases. J Exp Med 200:273–276
Tommasini A, Ferrari S, Moratto D, Badolato R, Boniotto M, Pirulli D, Notarangelo LD, Andolina M (2002) X-chromosome inactivation analysis in a female carrier of FOXP3 mutation. Clin Exp Immunol 130:127–130
Owen CJ, Jennings CE, Imrie H, Lachaux A, Bridges NA, Cheetham TD, Pearce SH (2003) Mutational analysis of the FOXP3 gene and evidence for genetic heterogeneity in the immunodysregulation, polyendocrinopathy, enteropathy syndrome. J Clin Endocrinol Metab 88:6034–6039
Sakaguchi S, Sakaguchi N (1994) Thymus, T cells, and autoimmunity: various causes but a common mechanism of autoimmune disease. In: Autoimmunity: physiology and diseases. Wiley-Liss, Hoboken NJ, pp 203–227
Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow DB, Hunter KM, Smith AN, Di Genova G, Herr MH, Dahlman I, Payne F, Smyth D, Lowe C, Twells RC, Howlett S, Healy B, Nutland S, Rance HE, Everett V, Smink LJ, Lam AC, Cordell HJ, Walker NM, Bordin C, Hulme J, Motzo C, Cucca F, Hess JF, Metzker ML, Rogers J, Gregory S, Allahabadia A, Nithiyananthan R, Tuomilehto-Wolf E, Tuomilehto J, Bingley P, Gillespie KM, Undlien DE, Ronningen KS, Guja C, Ionescu-Tirgoviste C, Savage DA, Maxwell AP, Carson DJ, Patterson CC, Franklyn JA, Clayton DG, Peterson LB, Wicker LS, Todd JA, Gough SC (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–511
Encinas JA, Wicker LS, Peterson LB, Mukasa A, Teuscher C, Sobel R, Weiner HL, Seidman CE, Seidman JG, Kuchroo VK (1999) QTL influencing autoimmune diabetes and encephalomyelitis map to a 0.15-cM region containing Il2. Nat Genet 21:158–160
Sakaguchi S, Sakaguchi N (1989) Organ-specific autoimmune disease induced in mice by elimination of T cell subsets. V. Neonatal administration of cyclosporin A causes autoimmune disease. J Immunol 142:471–480
Morse SS, Sakaguchi N, Sakaguchi S (1999)Virus and autoimmunity: induction of autoimmune disease in mice by mouse T lymphotropic virus (MTLV) destroying CD4+ T cells. J Immunol 162:5309–5316
Sakaguchi N, Miyai K, Sakaguchi S (1994) Ionizing radiation and autoimmunity. Induction of autoimmune disease inmiceby highdose fractionated total lymphoid irradiation and its prevention by inoculating normal T cells. J Immunol 152:2586–2595
Sakaguchi S, Ermak TH, Toda M, Berg LJ, Ho W, Fazekas de St Groth B, Peterson PA, Sakaguchi N, Davis MM (1994) Induction of autoimmune disease in mice by germline alteration of the T cell receptor gene expression. J Immunol 152:1471–1484
Fisson S, Darrasse-Jeze G, Litvinova E, Septier F, Klatzmann D, Liblau R, Salomon BL (2003) Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J Exp Med 198:737–746
Ginsberg-Fellner F, Witt ME, Fedun B, Taub F, Dobersen MJ, McEvoy RC, Cooper LZ, Notkins AL, Rubinstein P (1985) Diabetes mellitus and autoimmunity in patients with the congenital rubella syndrome. Rev Infect Dis 7[Suppl 1]:S170–S176
Sakaguchi S (2000) Animal models of autoimmunity and their relevance to human diseases. Curr Opin Immunol 12:684–690
Sakaguchi S, Sakaguchi N (2000) Role of genetic factors in organ-specific autoimmune diseases induced by manipulating the thymus or T cells, and not self-antigens. Rev Immunogenet 2:147–153
Fowell D, Mason D (1993) 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 177:627–636
Reddy J, Illes Z, Zhang X, Encinas J, Pyrdol J, Nicholson L, Sobel RA, Wucherpfennig KW, Kuchroo VK (2004) Myelin proteolipid protein-specific CD4+CD25+ regulatory cells mediate genetic resistance to experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 101:15434–15439
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Sakaguchi, S., Setoguchi, R., Yagi, H., Nomura, T. (2006). Naturally Arising Foxp3-Expressing CD25+CD4+ Regulatory T Cells in Self-Tolerance and Autoimmune Disease. In: Radbruch, A., Lipsky, P.E. (eds) Current Concepts in Autoimmunity and Chronic Inflammation. Current Topics in Microbiology and Immunology, vol 305. Springer, Berlin, Heidelberg . https://doi.org/10.1007/3-540-29714-6_3
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DOI: https://doi.org/10.1007/3-540-29714-6_3
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