Foxp3+CD25+CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease

Immunological Reviews

Volumn 212, Issue , 2006, Pages 8-27

  Sakaguchi, Shimon ^a,b   Ono, Masahiro ^a   Setoguchi, Ruka ^a,d   Yagi, Haruhiko ^a   Hori, Shohei ^a,e   Fehervari, Zoltan ^a,f   Shimizu, Jun ^c   Takahashi, Takeshi ^a,g   Nomura, Takashi ^a  

^a KYOTO UNIVERSITY   (Japan)

^b JAPAN SCIENCE AND TECHNOLOGY AGENCY   (Japan)

^c NATIONAL CENTER FOR GERIATRICS AND GERONTOLOGY   (Japan)

^d UNIVERSITY OF WASHINGTON   (United States)

^e INST OF PHYS AND CHEMICAL RESEARCH   (Japan)

^f UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^g DEUTSCHES RHEUMA FORSCHUNGSZENTRUM   (Germany)

Author keywords

Autoimmune disease; CD25; Foxp3; GITR; Immunologic tolerance; Regulatory T cells

Indexed keywords

CD4 ANTIGEN; CD40 ANTIGEN; CYTOKINE; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; GLUCOCORTICOID INDUCED TUMOR NECROSIS FACTOR RECEPTOR; INTERLEUKIN 2; INTERLEUKIN 2 RECEPTOR; INTERLEUKIN 2 RECEPTOR ALPHA; PROTEIN; TRANSCRIPTION FACTOR FOXP3; UNCLASSIFIED DRUG;

ADDISON DISEASE; ALLERGY; AUTOIMMUNE DISEASE; CELL DIFFERENTIATION; CELL FUNCTION; CELL MATURATION; CELL SURVIVAL; CYTOKINE PRODUCTION; ENVIRONMENTAL FACTOR; GENE MUTATION; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; GRAVES DISEASE; HASHIMOTO DISEASE; HEREDITY; HUMAN; IMMUNE DEFICIENCY; IMMUNE RESPONSE; IMMUNE SYSTEM; IMMUNOLOGICAL TOLERANCE; IMMUNOSTIMULATION; MOLECULAR CLONING; MOLECULAR MIMICRY; MOLECULAR RECOGNITION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION; STATISTICAL SIGNIFICANCE; T CELL DEPLETION; T LYMPHOCYTE ACTIVATION; T LYMPHOCYTE SUBPOPULATION; THYMUS;

ANIMALS; ANTIGENS, CD4; AUTOIMMUNE DISEASES; FORKHEAD TRANSCRIPTION FACTORS; HUMANS; LYMPHOCYTE ACTIVATION; MICE; RECEPTORS, INTERLEUKIN-2; SELF TOLERANCE; T-LYMPHOCYTES, REGULATORY;

EID: 33746342994     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/j.0105-2896.2006.00427.x     Document Type: Review

References (154)

1. Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004;22:531-562.
2. Shevach EM. Regulatory T cells in autoimmmunity. Annu Rev Immunol 2000;18:423-4-49.
3. Maloy KJ, Powrie F. Regulatory T cells in the control of immune pathology. Nat Immunol 2001;2:816-822.
4. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. 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 1995;155:1151-1164.
5. Singh B, et al. Control of intestinal inflammation by regulatory T cells. Immunol Rev 2001;182:190-200.
6. Itoh M, et al. 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 1999;162:5317-5326.
7. Seddon B, Mason D. The third function of the thymus. Immunol Today 2000;21:95-99.
8. Chen W, 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 2003;198:1875-1886.
9. Apostolou I, Von Boehmer H. In vivo instruction of suppressor commitment in naive T cells. J Exp Med 2004;199: 1401-1408.
10. Jordan MS, et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat Immunol 2001;2:301-306.
11. Hsieh CS, Zheng Y, Liang Y, Fontenot JD, Rudensky AY. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol 2006;7:401-410.
12. + regulatory T cells: implications of their broad repertoire and high self-reactivity for the maintenance of immunological self-tolerance. Novartis Found Symp 2003;252:6-16.
13. + regulatory T cells in the steady state. J Exp Med 2003;198:737-746.
14. Takahashi T, et al. Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol 1998;10:1969-1980.
15. 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.
16. von Boehmer H. Mechanisms of suppression by suppressor T cells. Nat Immunol 2005;6:338-344.
17. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057-1061.
18. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330-336.
19. 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.
20. Brunkow ME, 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.
21. Chatila TA, et al. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest 2000;106:R75-R81.
22. Wildin RS, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 2001;27:18-20.
23. Bennett CL, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001;27:20-21.
24. Yagi H, et al. Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. Int Immunol 2004;16:1643-1656.
25. Jaeckel E, von Boehmer H, Manns MP. Antigen-specific FoxP3-transduced T-cells can control established type 1 diabetes. Diabetes 2005;54:306-310.
26. Loser K, Hansen W, Apelt J, Balkow S, Buer J, Beissert S. In vitro-generated regulatory T cells induced by Foxp3-retrovirus infection control murine contact allergy and systemic autoimmunity. Gene Ther 2005;12:1294-1304.
27. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 2005;22:329-341.
28. Chang X, et al. The Scurfy mutation of FoxP3 in the thymus stroma leads to defective thymopoiesis. J Exp Med 2005;202:1141-1151.
29. Fontenot JD, Dooley JL, Farr AG, Rudensky AY. Developmental regulation of Foxp3 expression during ontogeny. J Exp Med 2005;202:901-906.
30. 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.
31. Ochs HD, Ziegler SF, Torgerson TR. FOXP3 acts as a rheostat of the immune response. Immunol Rev 2005;203:156-164.
32. 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.
33. - regulatory T cells. J Immunol 2006;176:4748-4756.
34. Kanangat S, et al. Disease in the scurfy (sf) mouse is associated with overexpression of cytokine genes. Eur J Immunol 1996;26:161-165.
35. You S, Slehoffer G, Barriot S, Bach JF, Chatenoud L. Unique role of CD4+CD62L+ regulatory T cells in the control of autoimmune diabetes in T cell receptor transgenic mice. Proc Nad Acad Sci USA 2004;101:14580-14585.
36. Sakaguchi S, Sakaguchi N. Role of genetic factors in organ-specific autoimmune diseases induced by manipulating the thymus or T cells, and not self-antigens. Rev Immunogenet 2000;2:147-153.
37. Limas CJ, lakovis P, Anyfantakis A, Kroupis C, Cokkinos DV. Familial clustering of autoimmune diseases in patients with dilated cardiomyopathy. Am J Cardiol 2004;93:1189-1191.
38. Tommasini A, et al. X-chromosome inactivation analysis in a female carrier of FOXP3 mutation. Clin Exp Immunol 2002;130:127-130.
39. Owen CJ, et al. Mutational analysis of the FOXP3 gene and evidence for genetic heterogeneity in the immunodysregulation, polyendocrinopathy, enteropathy syndrome. J Clin Endocrinol Metab 2003;88:6034-6039.
40. Dante NA, Koelle DM, Yee C, Beheray S, Kwok WW. Autoreactive T cells in healthy individuals. J Immunol 2004;172:5967-5972.
41. Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet 2002;39:537-545.
42. Sakaguchi S, Sakaguchi N. Thymus, T cells and autoimmunity: various causes but a common mechanism of autoimmune disease. In: Coutinho A, Kazatchkine M, eds. Autoimmunity: Physiology and Disease. New York: Wiley-Liss, 1994: 203-227.
43. Takahata Y, et al. CD25+CD4+ T cells in human cord blood: an immunoregulatory subset with naive phenotype and specific expression of forkhead box p3 (Foxp3) gene. Exp Hematol 2004;32:622-629.
44. Darrasse-Jeze G, Marodon G, Salomon BL, Catala M, Klatzmann D. Ontogeny of CD4+CD25+ regulatory/suppressor T cells in human fetuses. Blood 2005;105:4715-4721.
45. Schorle H, Holtschke T, Hunig T, Schimpl A, Horak I. Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 1991;352:621-624.
46. Horak I, Lohler J, Ma A, Smith KA. Interleukin-2 deficient mice: a new model to study autoimmunity and self-tolerance. Immunol Rev 1995;148:35-44.
47. Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW. Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 1995;3:521-530.
48. Suzuki H, Zhou YW, Kato M, Mak TW, Nakashima I. Normal regulatory alpha/beta T cells effectively eliminate abnormally activated T cells lacking the interleukin 2 receptor beta in vivo. J Exp Med 1999;190:1561-1572.
49. Sharfe N, Dadi HK, Shahar M, Roifman CM. Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. Proc Natl Acad Sci USA 1997;94:3168-3171.
50. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 2005;6:1142-1151.
51. Wolf M, Schimpl A, Hunig T. 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 2001;31:1637-1645.
52. Malek TR, Yu A, Vincek V, Scibelli P, Kong L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity 2002;17:167-178.
53. Almeida AR, Legrand N, Papiernik M, Freitas AA. 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 2002;169: 4850-4860.
54. D'Cruz LM, Klein L. Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat Immunol 2005;6:1152-1159.
55. Thornton AM, Donovan EE, Piccirillo CA, Shevach EM. Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J Immunol 2004;172:6519-6523.
56. Setoguchi R, Hori S, Takahashi T, Sakaguchi S. 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 2005;201:723-735.
57. + T cells. Proc Natl Acad Sci USA 2002;99:8832-8837.
58. Ohashi PS. Negative selection and autoimmunity. Curr Opin Immunol 2003;15:668-676.
59. Encinas JA, et al. QTL influencing autoimmune diabetes and encephalomyelitis map to a 0.15-cM region containing 112. Nat Genet 1999;21:158-160.
60. Podolin PL, et al. Differential glycosylation of interleukin 2, the molecular basis for the NOD Idd3 type 1 diabetes gene? Cytokine 2000;12:477-482.
61. Maier LM, Wicker LS. Genetic susceptibility to type 1 diabetes. Curr Opin Immunol 2005;17:601-608.
62. Vella A, et al. Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am J Hum Genet 2005;76:773-779.
63. Antov A, Yang L, Vig M, Baltimore D, Van Parijs L. Essential role for STAT5 signaling in CD25+CD4+ regulatory T cell homeostasis and the maintenance of self-tolerance. J Immunol 2003;171:3435-3441.
64. Burchill MA, et al. Distinct effects of STAT5 activation on CD4+ and CD8+ T cell homeostasis: development of CD4+CD25+ regulatory T cells versus CD8+ memory T cells. J Immunol 2003;171:5853-5864.
65. Sakaguchi S, Sakaguchi N. Organ-specific autoimmune disease induced in mice by elimination of T cell subsets. V. Neonatal administration of cyclosporin A causes autoimmune disease. J Immunol 1989;142:471-480.
66. Glazier A, Tutschka PJ, Farmer ER, Santos GW. Graft-versus-host disease in cyclosporin A-treated rats after syngeneic and autologous bone marrow reconstitution. J Exp Med 1983;158:1-8.
67. Hess AD. Modulation of graft-versus-host disease: role of regulatory T lymphocytes. Biol Blood Marrow Transplant 2006;12(Suppl. 2):13-21.
68. Fehervari Z, Yamaguchi T, Sakaguchi S. The dichotomous role of IL-2: tolerance versus immunity. Trends Immunol 2006;27:109-111.
69. Knoechel B, Lohr J, Kahn E, Bluestone JA, Abbas AK. Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen. J Exp Med 2005;202:1375-1386.
70. Yamazaki S, et al. Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J Exp Med 2003;198:235-247.
71. Tang Q, et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 2004;199:1455-1465.
72. Nishimura E, Sakihama T, Setoguchi R, Tanaka K, Sakaguchi S. Induction of antigen-specific immunologic tolerance by in vivo and in vitro antigen-specific expansion of naturally arising Foxp3+CD25+CD4+ regulatory T cells. Int Immunol 2004;16:1189-1201.
73. Takahashi T, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000;192:303-310.
74. Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 2000;192:295-302.
75. Salomon B, 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.
76. Tang Q, Boden EK, Henriksen KJ, Bour-Jordan H, Bi M, Bluestone JA. Distinct roles of CTLA-4 and TGF-beta in CD4+CD25+ regulatory T cell function. Eur J Immunol 2004;34:2996-3005.
77. Luhder F, Hoglund P, Allison JP, Benoist C, Mathis D. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes. J Exp Med 1998;187:427-432.
78. Tivol EA, Gorski J. Re-establishing peripheral tolerance in the absence of CTLA-4: complementation by wild-type T cells points to an indirect role for CTLA-4. J Immunol 2002;169:1852-1858.
79. Grohmann U, et al. CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 2002;3:1097-1101.
80. Fallarino F, et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 2003;4:1206-1212.
81. Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 2004;4:762-774.
82. Paust S, Lu L, McCarty N, Cantor H. Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease. Proc Natl Acad Sci USA 2004;101:10398-10403.
83. Schneider H, Valk E, da Rocha Dias S, Wei B, Rudd CE. CTLA-4 up-regulation of lymphocyte function-associated antigen 1 adhesion and clustering as an alternate basis for coreceptor function. Proc Natl Acad Sci USA 2005;102:12861-12866.
84. Phan GQ, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 2003;100:8372-8377.
85. Atabani SF, et al. Association of CTLA4 polymorphism with regulatory T cell frequency. Eur J Immunol 2005;35:2157-2162.
86. Vijayakrishnan L, et al. An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells. Immunity 2004;20:563-575.
87. Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 2002;3:135-142.
88. McHugh RS, 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.
89. Nocentini G, Riccardi C. GITR: a multifaceted regulator of immunity belonging to the tumor necrosis factor receptor superfamily. Eur J Immunol 2005;35:1016-1022.
90. Stephens GL, et al. Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T Cells. J Immunol 2004;173:5008-5020.
91. Ji HB, et al. Cutting edge: the natural ligand for glucocorticoid-induced TNF receptor-related protein abrogates regulatory T cell suppression. J Immunol 2004;172:5823-5827.
92. Tone M, et al. Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells. Proc Natl Acad Sci USA 2003;100:15059-15064.
93. Kumanogoh A, et al. Increased T cell autoreactivity in the absence of CD40-CD40 ligand interactions: a role of CD40 in regulatory T cell development. J Immunol 2001;166:353-360.
94. Serra P, et al. CD40 ligation releases immature dendritic cells from the control of regulatory CD4+CD25+ T cells. Immunity 2003;19:877-889.
95. Guiducci C, Valzasina B, Dislich H, Colombo MP. CD40/CD40L interaction regulates CD4+CD25+ T reg homeostasis through dendritic cell-produced IL-2. Eur J Immunol 2005;35:557-567.
96. Quezada SA, Jarvinen LZ, Lind EF, Noelle RJ. CD40/CD154 interactions at the interface of tolerance and immunity. Annu Rev Immunol 2004;22:307-328.
97. Wohlfert EA, Callahan MK, Clark RB. Resistance to CD4+CD25+ regulatory T cells and TGF-beta in Cbl-b-/- mice. J Immunol 2004;173:1059-1065.
98. Wohlfert EA, Gorelik L, Mittler R, Flavell RA, Clark RB. Cutting edge: deficiency in the E3 ubiquitin ligase Cbl-b results in a multifunctional defect in T cell TGF-beta sensitivity in vitro and in vivo. J Immunol 2006;176:1316-1320.
99. Yokoi N, et al. Cblb is a major susceptibility gene for rat type 1 diabetes mellitus. Nat Genet 2002;31:391-394.
100. Bopp T, et al. NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+ T lymphocytes by CD4+ CD25+ regulatory T cells. J Exp Med 2005;201:181-187.
101. Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2003;299:1033-1036.
102. Fehervari Z, Sakaguchi S. Control of Foxp3+ CD25+CD4+ regulatory cell activation and function by dendritic cells. Int Immunol 2004;16:1769-1780.
103. Marie JC, Letterio JJ, Gavin M, Rudensky AY. TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med 2005;201:1061-1067.
104. Schramm C, et al. TGFbeta regulates the CD4+CD25+ T-cell pool and the expression of Foxp3 in vivo. Int Immunol 2004;16:1241-1249.
105. Huber S, et al. Cutting edge: TGF-beta signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+CD25+ T cells. J Immunol 2004;173:6526-6531.
106. Fahlen L, et al. T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells. J Exp Med 2005;201:737-746.
107. Sakaguchi N, et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 2003;426:454-460.
108. Aguado E, et al. Induction of T helper type 2 immunity by a point mutation in the LAT adaptor. Science 2002;296:2036-2040.
109. Sommers CL, et al. A LAT mutation that inhibits T cell development yet induces lymphoproliferation. Science 2002;296:2040-2043.
110. Sommers CL, et al. Mutation of the phospholipase C-gamma1-binding site of LAT affects both positive and negative thymocyte selection. J Exp Med 2005;201:1125-1134.
111. Koonpaew S, Shen S, Flowers L, Zhang W. LAT-mediated signaling in CD4+CD25+ regulatory T cell development. J Exp Med 2006;203:119-129.
112. Ramsey C, et al. Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum Mol Genet 2002;11:397-409.
113. Anderson MS, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 2002;298:1395-1401.
114. Kuroda N, et al. Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice. J Immunol 2005;174:1862-1870.
115. Derbinski J, et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med 2005;202:33-45.
116. Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC. Aire regulates negative selection of organ-specific T cells. Nat Immunol 2003;4:350-354.
117. Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D. The cellular mechanism of Aire control of T cell tolerance. Immunity 2005;23:227-239.
118. Kajiura F, et al. NF-kappa B-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner. J Immunol 2004;172:2067-2075.
119. Akiyama T, et al. Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science 2005;308:248-251.
120. Ramsey C, et al. Increased antigen presenting cell-mediated T cell activation in mice and patients without the autoimmune regulator. Eur J Immunol 2006;36:305-317.
121. Eriksson U, et al. Dendritic cell-induced autoimmune heart failure requires cooperation between adaptive and innate immunity. Nat Med 2003;9:1484-1490.
122. Watanabe H, et al. Experimental autoimmune thyroiditis induced by thyroglobulin-pulsed dendritic cells. Autoimmunity 1999;31:273-282.
123. McGeachy MJ, Stephens LA, Anderton SM. Natural recovery and protection from autoimmune encephalomyelitis. contribution of CD4+CD25+ regulatory cells within the central nervous system. J Immunol 2005;175:3025-3032.
124. Kohm AP, Carpentier PA, Anger HA, Miller SD. Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol 2002;169:4712-4716.
125. Morris GP, Yan Y, David CS, Kong YC. H2A-and H2E-derived CD4+CD25+ regulatory T cells: a potential role in reciprocal inhibition by class II genes in autoimmune thyroiditis. J Immunol 2005;174:3111-3116.
126. Reddy J, et al. Myelin proteolipid protein-specific CD4+CD25+ regulatory cells mediate genetic resistance to experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 2004;101:15434-15439.
127. Mason D. A very high level of crossreactivity is an essential feature of the T-cell receptor. Immunol Today 1998;19:395-404.
128. Hemmer B, Vergelli M, Pinilla C, Houghten R, Martin R. Probing degeneracy in T-cell recognition using peptide combinatorial libraries. Immunol Today 1998;19:163-168.
129. Wucherpfennig KW. Mechanisms for the induction of autoimmunity by infectious agents. J Clin Invest 2001;108:1097-1104.
130. Sakaguchi S. Policing the regulators. Nat Immunol 2001;2:283-284.
131. Stephens LA, Gray D, Anderton SM. CD4+CD25+ regulatory T cells limit the risk of autoimmune disease arising from T cell receptor crossreactivity. Proc Natl Acad Sci USA 2005;102:17418-17423.
132. Wucherpfennig KW, Strominger JL. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 1995;80:695-705.
133. Mordes JP, et al. The BB/Wor rat and the balance hypothesis of autoimmunity. Diabetes Metab Rev 1996;12:103-109.
134. MacMurray AJ, et al. Lymphopenia in the BB rat model of type 1 diabetes is due to a mutation in a novel immune-associated nucleotide (Ian)-related gene. Genome Res 2002;12:1029-1039.
135. Poussier P, Ning T, Murphy T, Dabrowski D, Ramanathan S. Impaired post-thymic development of regulatory CD4+25+ T cells contributes to diabetes pathogenesis in BB rats. J Immunol 2005;174:4081-4089.
136. Buse JB, Ben-Nun A, Klein KA, Eisenbarth GS, Seidman JG, Jackson RA. Specific class II histocompatibility gene polymorphism in BB rats. Diabetes 1984;33:700-703.
137. Penhale WJ, Farmer A, Irvine WJ. Thyroiditis in T cell-depleted rats. Influence of strain, radiation dose, adjuvants and antilymphocyte serum. Clin Exp Immunol 1975;21:362-375.
138. 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.
139. Sakaguchi S. Animal models of autoimmunity and their relevance to human diseases. Curr Opin Immunol 2000;12:684-690.
140. Todd JA, Wicker LS. Genetic protection from the inflammatory disease type 1 diabetes in humans and animal models. Immunity 2001;15:387-395.
141. Gregori S, Giarratana N, Smiroldo S, Adorini L. Dynamics of pathogenic and suppressor T cells in autoimmune diabetes development. J Immunol 2003;171:4040-4047.
142. Braley-Mullen H, Sharp GC, Medling B, Tang H. Spontaneous autoimmune thyroiditis in NOD.H-2h4 mice. J Autoimmun 1999;12:157-165.
143. Elliott JF, et al. Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAbeta knockout NOD mice. Proc Natl Acad Sci USA 2003;100:13447-13452.
144. Taylor JA, Havari E, McInerney MF, Bronson R, Wucherpfennig KW, Lipes MA. A spontaneous model for autoimmune myocarditis using the human MHC molecule HLA-DQ8. J Immunol 2004;172:2651-2658.
145. Sakaguchi N, Miyai K, Sakaguchi S. Ionizing radiation and autoimmunity. Induction of autoimmune disease in mice by high dose fractionated total lymphoid irradiation and its prevention by inoculating normal T cells. J Immunol 1994;152:2586-2595.
146. Morse SS, Sakaguchi N, Sakaguchi S. Virus and autoimmunity: induction of autoimmune disease in mice by mouse T lymphotropic virus (MTLV) destroying CD4+ T cells. J Immunol 1999;162:5309-5316.
147. Sakaguchi S, et al. Induction of autoimmune disease in mice by germline alteration of the T cell receptor gene expression. J Immunol 1994;152:1471-1484.
148. Barrett SP, Toll BH, Alderuccio F, van Driel IR, Gleeson PA. Organ-specific autoimmunity induced by adult thymectomy and cyclophosphamide- induced lymphopenia. Eur J Immunol 1995;25:238-244.
149. Bottini N, et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 2004;36:337-378.
150. Vang T, et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet 2005;37:1317-1319.
151. Kriegel MA, Lohmann T, Gabler C, Blank N, Kalden JR, Lorenz HM. Defective suppressor function of human CD4+ CD25+ regulatory T cells in autoimmune polyglandular syndrome type II. J Exp Med 2004;199:1285-1291.
152. Sullivan KE, McDonald-McGinn D, Zackai EH. CD4(+) CD25(+) T-cell production in healthy humans and in patients with thymic hypoplasia. Clin Diagn Lab Immunol 2002;9:1129-1131.
153. Forrest JM, Menser MA, Burgess JA. High frequency of diabetes mellitus in young adults with congenital rubella. Lancet 1971;2:332-334.
154. Gianani R, Eisenbarth GS. The stages of type 1A diabetes: 2005. Immunol Rev 2005;204:232-249.