Functional dynamics of Foxp3+ regulatory T cells in mice and humans

Immunological Reviews

Volumn 259, Issue 1, 2014, Pages 140-158

  Bin Dhuban, Khalid ^a   Kornete, Mara ^a   Mason, Edward S ^a   Piccirillo, Ciriaco A ^a  

^a RESEARCH INSTITUTE OF THE MCGILL UNIVERSITY HEALTH CENTRE   (Canada)

Author keywords

Autoimmunity; Foxp3; Infections; Regulatory T cells; Tolerance

Indexed keywords

CD4 ANTIGEN; CHEMOKINE RECEPTOR CXCR3; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; GLYCOPROTEIN; GLYCOPROTEIN A REPETITIONS PREDOMINANT; HLA DR ANTIGEN; INTERLEUKIN 2; INTERLEUKIN 2 RECEPTOR ALPHA; INTERLEUKIN 7 RECEPTOR; TRANSCRIPTION FACTOR FOXP3; UNCLASSIFIED DRUG;

ARTICLE; CD25+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; CELL FUNCTION; CELL LINEAGE; CELL SURVIVAL; EXHAUSTION; GENE CONTROL; GENE EXPRESSION; HUMAN; IMMUNOMODULATION; INFLAMMATION; INFLAMMATORY BOWEL DISEASE; INSULIN DEPENDENT DIABETES MELLITUS; IPEX SYNDROME; MOUSE; MULTIPLE SCLEROSIS; NONHUMAN; NUCLEAR REPROGRAMMING; PLASTICITY; PRIORITY JOURNAL; PROTEIN HOMEOSTASIS; REGULATORY T LYMPHOCYTE; RHEUMATOID ARTHRITIS; RNA PROCESSING; RNA TRANSLATION; SIGNAL TRANSDUCTION; SYSTEMIC LUPUS ERYTHEMATOSUS;

AUTOIMMUNITY; FOXP3; INFECTIONS; REGULATORY T CELLS; TOLERANCE;

ANIMALS; BIOLOGICAL MARKERS; CELL DIFFERENTIATION; CELL LINEAGE; CELL MOVEMENT; CELL SURVIVAL; FORKHEAD TRANSCRIPTION FACTORS; GENE EXPRESSION REGULATION; HOMEOSTASIS; HUMANS; IMMUNOMODULATION; INFLAMMATION; MICE; PHENOTYPE; RNA PROCESSING, POST-TRANSCRIPTIONAL; T-LYMPHOCYTES, REGULATORY;

EID: 84897948864     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/imr.12168     Document Type: Article

References (206)

1. 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.
2. Lio CW, Hsieh CS. Becoming self-aware: the thymic education of regulatory T cells. Curr Opin Immunol 2011;23:213-219.
3. Klein L, Jovanovic K. Regulatory T cell lineage commitment in the thymus. Semin Immunol 2011;23:401-409.
4. 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.
5. Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol 2010;11:7-13.
6. Piccirillo CA, d'Hennezel E, Sgouroudis E, Yurchenko E. CD4+Foxp3+ regulatory T cells in the control of autoimmunity: in vivo veritas. Curr Opin Immunol 2008;20:655-662.
7. Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev 2011;241:260-268.
8. Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 2009;30:636-645.
9. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330-336.
10. Hori S, Sakaguchi S. Foxp3: a critical regulator of the development and function of regulatory T cells. Microbes Infect 2004;6:745-751.
11. 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.
12. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057-1061.
13. 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.
14. Ochs HD, Ziegler SF, Torgerson TR. FOXP3 acts as a rheostat of the immune response. Immunol Rev 2005;203:156-164.
15. 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.
16. Gambineri E, Torgerson TR, Ochs HD. 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 2003;15:430-435.
17. 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.
18. Tommasini A, et al. X-chromosome inactivation analysis in a female carrier of FOXP3 mutation. Clin Exp Immunol 2002;130:127-130.
19. 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.
20. 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.
21. Mucida D, et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 2007;317:256-260.
22. Tran DQ, Ramsey H, Shevach EM. Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype. Blood 2007;110:2983-2990.
23. Walker LSK, Chodos A, Eggena M, Dooms H, Abbas AK. Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J Exp Med 2003;198:249-258.
24. Wang J, Ioan-Facsinay A, van der Voort EIH, Huizinga TWJ, Toes REM. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol 2007;37:129-138.
25. Khattri R, et al. The amount of scurfin protein determines peripheral T cell number and responsiveness. J Immunol 2001;167:6312-6320.
26. Lal G, et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol 2009;182:259-273.
27. Lin W, et al. Regulatory T cell development in the absence of functional Foxp3. Nat Immunol 2007;8:359-368.
28. Gavin MA, et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 2007;445:771-775.
29. Hill JA, et al. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity 2007;27:786-800.
30. Sugimoto N, et al. Foxp3-dependent and -independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis. Int Immunol 2006;18:1197-1209.
31. Zheng Y, Josefowicz SZ, Kas A, Chu T-T, Gavin MA, Rudensky AY. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 2007;445:936-940.
32. Lahl K, et al. Nonfunctional regulatory T cells and defective control of Th2 cytokine production in natural scurfy mutant mice. J Immunol 2009;183:5662-5672.
33. Samstein RM, et al. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 2012;151:153-166.
34. Bilate AM, Lafaille JJ. Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu Rev Immunol 2012;30:733-758.
35. 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.
36. Bjur E, et al. Distinct translational control in CD4+ T cell subsets. PLoS Genet 2013;9:e1003494.
37. Anderson MS, Bluestone JA. The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 2005;23:447-485.
38. Chatenoud L, Bach JF. Regulatory T cells in the control of autoimmune diabetes: the case of the NOD mouse. Int Rev Immunol 2005;24:247-267.
39. Chen Z, Herman AE, Matos M, Mathis D, Benoist C. Where CD4+CD25+ T reg cells impinge on autoimmune diabetes. J Exp Med 2005;202:1387-1397.
40. 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.
41. 2-deficient mice: implications for the nonredundant function of IL-2. Immunity 2002;17:167-178.
42. Cheng G, Yu A, Malek TR. T-cell tolerance and the multi-functional role of IL-2R signaling in T-regulatory cells. Immunol Rev 2011;241:63-76.
43. Ono M, et al. Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 2007;446:685-689.
44. Sgouroudis E, Albanese A, Piccirillo CA. Impact of protective IL-2 allelic variants on CD4+Foxp3+ regulatory T cell function in situ and resistance to autoimmune diabetes in NOD mice. J Immunol 2008;181:6283-6292.
45. Tang Q, et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 2008;28:687-697.
46. Yamanouchi J, et al. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat Genet 2007;39:329-337.
47. Klein LMDCL. Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat Immunol 2005;6:1152-1159.
48. 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.
49. Long SA, et al. Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4+CD25+ regulatory T-cells of type 1 diabetic subjects. Diabetes 2010;59:407-415.
50. Kornete M, Sgouroudis E, Piccirillo CA. ICOS-dependent homeostasis and function of Foxp3+ regulatory T cells in islets of nonobese diabetic mice. J Immunol 2012;188:1064-1074.
51. 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.
52. Barron L, et al. Cutting edge: mechanisms of IL-2â€"dependent maintenance of functional regulatory T cells. J Immunol 2010;185:6426-6430.
53. Grinberg-Bleyer Y, et al. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J Exp Med 2010;207:1871-1878.
54. Ounissi-Benkalha H, Polychronakos C. The molecular genetics of type 1 diabetes: new genes and emerging mechanisms. Trends Mol Med 2008;14:268-275.
55. Sgouroudis E, Kornete M, Piccirillo CA. IL-2 production by dendritic cells promotes Foxp3(+) regulatory T-cell expansion in autoimmune-resistant NOD congenic mice. Autoimmunity 2011;44:406-414.
56. Maine CJ, et al. PTPN22 alters the development of regulatory T cells in the thymus. J Immunol 2012;188:5267-5275.
57. Darrasse-JÃ̈ze G, et al. Feedback control of regulatory T cell homeostasis by dendritic cells in vivo. J Exp Med 2009;206:1853-1862.
58. Bt Salomon, 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.
59. Tang Q, et al. Cutting edge: CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. J Immunol 2003;171:3348-3352.
60. Busse M, Krech M, Meyer-Bahlburg A, Hennig C, Hansen G. ICOS mediates the generation and function of CD4+CD25+Foxp3+ regulatory T cells conveying respiratory tolerance. J Immunol 2012;189:1975-1982.
61. Galicia G, Kasran A, Uyttenhove C, Swert K, Snick J, Ceuppens J. ICOS deficiency results in exacerbated IL-17 mediated experimental autoimmune encephalomyelitis. J Clin Immunol 2009;29:426-433.
62. Botturi K, Lacoeuille Y, CavaillÃ̈s A, Vervloet D, Magnan A. Differences in allergen-induced T cell activation between allergic asthma and rhinitis: role of CD28, ICOS and CTLA-4. Respir Res 2011;12:1-10.
63. Dong C, Nurieva RI. Regulation of immune and autoimmune responses by ICOS. J Autoimmun 2003;21:255-260.
64. Sperling AI, Bluestone JA. ICOS costimulation: it's not just for TH2 cells anymore. Nat Immunol 2001;2:573-574.
65. Herman AE, Freeman GJ, Mathis D, Benoist C. CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J Exp Med 2004;199:1479-1489.
66. Prevot N, et al. Abrogation of ICOS/ICOS ligand costimulation in NOD mice results in autoimmune deviation toward the neuromuscular system. Eur J Immunol 2010;40:2267-2276.
67. Pruul K, et al. Expression of B7 and CD28 family genes in newly diagnosed type 1 diabetes. Hum Immunol 2013;74:1251-1257.
68. Simpson TR, Quezada SA, Allison JP. Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS). Curr Opin Immunol 2010;22:326-332.
69. Lã¶hning M, et al. Expression of ICOS in vivo defines CD4+ effector T cells with high inflammatory potential and a strong bias for secretion of interleukin 10. J Exp Med 2003;197:181-193.
70. Warnatz K, et al. Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood 2006;107:3045-3052.
71. Zhang N, et al. Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response. Immunity 2009;30:458-469.
72. Wysocki CA, et al. Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease. Blood 2005;106:3300-3307.
73. Yurchenko E, Tritt M, Hay V, Shevach EM, Belkaid Y, Piccirillo CA. CCR5-dependent homing of naturally occurring CD4+ regulatory T cells to sites of Leishmania major infection favors pathogen persistence. J Exp Med 2006;203:2451-2460.
74. Tan MC, et al. Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol 2009;182:1746-1755.
75. Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 2009;10:595-602.
76. Erhardt A, et al. CXCR3 deficiency exacerbates liver disease and abrogates tolerance in a mouse model of immune-mediated hepatitis. J Immunol 2011;186:5284-5293.
77. Oo YH, et al. Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver. J Immunol 2010;184:2886-2898.
78. Redjimi N, et al. CXCR3+ T regulatory cells selectively accumulate in human ovarian carcinomas to limit type I immunity. Cancer Res 2012;72:4351-4360.
79. Yamazaki T, et al. CCR6 regulates the migration of inflammatory and regulatory T cells. J Immunol 2008;181:8391-8401.
80. Chaudhry A, et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 2009;326:986-991.
81. Zheng Y, et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 2009;458:351-356.
82. Huber S, et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3(-) and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 2011;34:554-565.
83. Suffia I, Reckling SK, Salay G, Belkaid Y. A role for CD103 in the retention of CD4+CD25+ Treg and control of leishmania major infection. J Immunol 2005;174:5444-5455.
84. Lehmann J, et al. Expression of the integrin αEβ7 identifies unique subsets of CD25+ as well as CD25- regulatory T cells. Proc Natl Acad Sci USA 2002;99:13031-13036.
85. Kunkel EJ, Campbell DJ, Butcher EC. Chemokines in lymphocyte trafficking and intestinal immunity. Microcirculation 2003;10:313-323.
86. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006;6:295-307.
87. Menetrier-Caux C, Curiel T, Faget J, Manuel M, Caux C, Zou W. Targeting regulatory T cells. Targeted Oncol 2012;7:15-28.
88. Facciabene A, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 2011;475:226-230.
89. Tan W, et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 2011;470:548-553.
90. Brenchley JM, et al. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood 2003;101:2711-2720.
91. Wherry EJ. T cell exhaustion. Nat Immunol 2011;12:492-499.
92. Tessmer MS, et al. KLRG1 binds cadherins and preferentially associates with SHIP-1. Int Immunol 2007;19:391-400.
93. GrÃndemann C, et al. Cutting edge: identification of E-cadherin as a ligand for the murine killer cell lectin-like receptor G1. J Immunol 2006;176:1311-1315.
94. Ito M, Maruyama T, Saito N, Koganei S, Yamamoto K, Matsumoto N. Killer cell lectin-like receptor G1 binds three members of the classical cadherin family to inhibit NK cell cytotoxicity. J Exp Med 2006;203:289-295.
95. Van Leeuwen EMM, De Bree GJ, Ten Berge IJM, Van Lier RAW. Human virus-specific CD8+ T cells: diversity specialists. Immunol Rev 2006;211:225-235.
96. Henson SM, et al. KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells. Blood 2009;113:6619-6628.
97. Zhou X, et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 2009;10:1000-1007.
98. Feuerer M, Hill JA, Kretschmer K, von Boehmer H, Mathis D, Benoist C. Genomic definition of multiple ex vivo regulatory T cell subphenotypes. Proc Natl Acad Sci USA 2010;107:5919-5924.
99. Tauro S, Nguyen P, Li B, Geiger TL. Diversification and senescence of Foxp3+ regulatory T cells during experimental autoimmune encephalomyelitis. Eur J Immunol 2013;43:1195-1207.
100. Yu A, Zhu L, Altman NH, Malek TR. A low interleukin-2 receptor signaling threshold supports the development and homeostasis of T regulatory cells. Immunity 2009;30:204-217.
101. Cheng G, Yuan X, Tsai MS, Podack ER, Yu A, Malek TR. IL-2 receptor signaling is essential for the development of Klrg1+ terminally differentiated T regulatory cells. J Immunol 2012;189:1780-1791.
102. Rubtsov YP, et al. Stability of the regulatory T cell lineage in vivo. Science 2010;329:1667-1671.
103. Ohkura N, et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 2012;37:785-799.
104. Chen Q, Kim YC, Laurence A, Punkosdy GA, Shevach EM. IL-2 controls the stability of Foxp3 expression in TGF-beta-induced Foxp3+ T cells in vivo. J Immunol 2011;186:6329-6337.
105. Komatsu N, Mariotti-Ferrandiz ME, Wang Y, Malissen B, Waldmann H, Hori S. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci USA 2009;106:1903-1908.
106. Pyzik M, Piccirillo CA. TGF-beta1 modulates Foxp3 expression and regulatory activity in distinct CD4+ T cell subsets. J Leukoc Biol 2007;82:335-346.
107. 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.
108. Duarte JH, Zelenay S, Bergman ML, Martins AC, Demengeot J. Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. Eur J Immunol 2009;39:948-955.
109. Yurchenko E, et al. Inflammation-driven reprogramming of CD4+ Foxp3+ regulatory T cells into pathogenic Th1/Th17 T effectors is abrogated by mTOR inhibition in vivo. PLoS ONE 2012;7:e35572.
110. Xu L, Kitani A, Fuss I, Strober W. Cutting edge: regulatory T cells induce CD4+CD25-Foxp3- T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta. J Immunol 2007;178:6725-6729.
111. Sharma MD, et al. Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity 2010;33:942-954.
112. Tsuji M, et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science 2009;323:1488-1492.
113. Murai M, et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol 2009;10:1178-1184.
114. Delgoffe GM, et al. Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 2013;501:252-256.
115. Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 2010;463:808-812.
116. Miyao T, et al. Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 2012;36:262-275.
117. d'Hennezel E, Yurchenko E, Sgouroudis E, Hay V, Piccirillo CA. Single-cell analysis of the human T regulatory population uncovers functional heterogeneity and instability within FOXP3+ cells. J Immunol 2011;186:6788-6797.
118. d'Hennezel E, Bin Dhuban K, Torgerson TR, Piccirillo CA. The immunogenetics of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet 2012;49:291-302.
119. d'Hennezel E, et al. FOXP3 forkhead domain mutation and regulatory T cells in the IPEX syndrome. N Engl J Med 2009;361:1710-1713.
120. Kukreja A, et al. Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest 2002;109:131-140.
121. Putnam AL, Vendrame F, Dotta F, Gottlieb PA. CD4+CD25high regulatory T cells in human autoimmune diabetes. J Autoimmun 2005;24:55-62.
122. Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TI. Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes 2005;54:92-99.
123. Brusko T, et al. No alterations in the frequency of FOXP3+ regulatory T-cells in type 1 diabetes. Diabetes 2007;56:604-612.
124. Brusko TM, Hulme MA, Myhr CB, Haller MJ, Atkinson MA. Assessing the in vitro suppressive capacity of regulatory T cells. Immunol Invest 2007;36:607-628.
125. Schneider A, Rieck M, Sanda S, Pihoker C, Greenbaum C, Buckner JH. The effector T cells of diabetic subjects are resistant to regulation via CD4+ FOXP3+ regulatory T cells. J Immunol 2008;181:7350-7355.
126. Lawson JM, et al. Increased resistance to CD4+CD25hi regulatory T cell-mediated suppression in patients with type 1 diabetes. Clin Exp Immunol 2008;154:353-359.
127. Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 2004;199:971-979.
128. Putheti P, Pettersson A, Soderstrom M, Link H, Huang YM. Circulating CD4+CD25+ T regulatory cells are not altered in multiple sclerosis and unaffected by disease-modulating drugs. J Clin Immunol 2004;24:155-161.
129. Haas J, et al. Prevalence of newly generated naive regulatory T cells (Treg) is critical for Treg suppressive function and determines Treg dysfunction in multiple sclerosis. J Immunol 2007;179:1322-1330.
130. Feger U, Luther C, Poeschel S, Melms A, Tolosa E, Wiendl H. Increased frequency of CD4+ CD25+ regulatory T cells in the cerebrospinal fluid but not in the blood of multiple sclerosis patients. Clin Exp Immunol 2007;147:412-418.
131. Michel L, et al. Patients with relapsing-remitting multiple sclerosis have normal Treg function when cells expressing IL-7 receptor alpha-chain are excluded from the analysis. J Clin Invest 2008;118:3411-3419.
132. Venken K, et al. Compromised CD4+ CD25(high) regulatory T-cell function in patients with relapsing-remitting multiple sclerosis is correlated with a reduced frequency of FOXP3-positive cells and reduced FOXP3 expression at the single-cell level. Immunology 2008;123:79-89.
133. Borsellino G, et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 2007;110:1225-1232.
134. Haas J, et al. Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. Eur J Immunol 2005;35:3343-3352.
135. Huan J, et al. Decreased FOXP3 levels in multiple sclerosis patients. J Neurosci Res 2005;81:45-52.
136. Astier AL, Meiffren G, Freeman S, Hafler DA. Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis. J Clin Invest 2006;116:3252-3257.
137. Saruta M, et al. Characterization of FOXP3+CD4+ regulatory T cells in Crohn's disease. Clin Immunol 2007;125:281-290.
138. Takahashi M, et al. An inverse correlation of human peripheral blood regulatory T cell frequency with the disease activity of ulcerative colitis. Digest Dis Sci 2006;51:677-686.
139. Maul J, et al. Peripheral and intestinal regulatory CD4+ CD25(high) T cells in inflammatory bowel disease. Gastroenterology 2005;128:1868-1878.
140. Rahman A, Fahlgren A, Sundstedt C, Hammarstrom S, Danielsson A, Hammarstrom ML. Chronic colitis induces expression of beta-defensins in murine intestinal epithelial cells. Clin Exp Immunol 2011;163:123-130.
141. Holmen N, et al. Functional CD4+CD25high regulatory T cells are enriched in the colonic mucosa of patients with active ulcerative colitis and increase with disease activity. Inflamm Bowel Dis 2006;12:447-456.
142. Yu QT, Saruta M, Avanesyan A, Fleshner PR, Banham AH, Papadakis KA. Expression and functional characterization of FOXP3+ CD4+ regulatory T cells in ulcerative colitis. Inflamm Bowel Dis 2007;13:191-199.
143. Kelsen J, Agnholt J, Hoffmann HJ, Romer JL, Hvas CL, Dahlerup JF. FoxP3(+)CD4(+)CD25(+) T cells with regulatory properties can be cultured from colonic mucosa of patients with Crohn's disease. Clin Exp Immunol 2005;141:549-557.
144. Makita S, et al. Intestinal lamina propria retaining CD4+CD25+ regulatory T cells is a suppressive site of intestinal inflammation. J Immunol 2007;178:4937-4946.
145. Cao D, van Vollenhoven R, Klareskog L, Trollmo C, Malmstrom V. CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease. Arthritis Res Ther 2004;6:R335-346.
146. Mottonen M, Heikkinen J, Mustonen L, Isomaki P, Luukkainen R, Lassila O. CD4+ CD25+ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis. Clin Exp Immunol 2005;140:360-367.
147. Lawson CA, et al. Early rheumatoid arthritis is associated with a deficit in the CD4+CD25high regulatory T cell population in peripheral blood. Rheumatology 2006;45:1210-1217.
148. Han GM, O'Neil-Andersen NJ, Zurier RB, Lawrence DA. CD4+CD25high T cell numbers are enriched in the peripheral blood of patients with rheumatoid arthritis. Cell Immunol 2008;253:92-101.
149. Cao D, et al. FOXP3 identifies regulatory CD25bright CD4+ T cells in rheumatic joints. Scand J Immunol 2006;63:444-452.
150. Cao D, Malmstrom V, Baecher-Allan C, Hafler D, Klareskog L, Trollmo C. Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur J Immunol 2003;33:215-223.
151. Ehrenstein MR, et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med 2004;200:277-285.
152. Crispin JC, Martinez A, Alcocer-Varela J. Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun 2003;21:273-276.
153. Miyara M, et al. Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol 2005;175:8392-8400.
154. Mellor-Pita S, et al. Decrease of regulatory T cells in patients with systemic lupus erythematosus. Ann Rheum Dis 2006;65:553-554.
155. Suen JL, Li HT, Jong YJ, Chiang BL, Yen JH. Altered homeostasis of CD4(+) FoxP3(+) regulatory T-cell subpopulations in systemic lupus erythematosus. Immunology 2009;127:196-205.
156. Lee JH, Wang LC, Lin YT, Yang YH, Lin DT, Chiang BL. Inverse correlation between CD4+ regulatory T-cell population and autoantibody levels in paediatric patients with systemic lupus erythematosus. Immunology 2006;117:280-286.
157. Venigalla RK, et al. Reduced CD4+, CD25- T cell sensitivity to the suppressive function of CD4+, CD25high, CD127-/low regulatory T cells in patients with active systemic lupus erythematosus. Arthritis Rheum 2008;58:2120-2130.
158. Alvarado-Sanchez B, et al. Regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun 2006;27:110-118.
159. Valencia X, Yarboro C, Illei G, Lipsky PE. Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol 2007;178:2579-2588.
160. Miyara M, Wing K, Sakaguchi S. Therapeutic approaches to allergy and autoimmunity based on FoxP3+ regulatory T-cell activation and expansion. J Allergy Clin Immunol 2009;123:749-755; quiz 756-747.
161. Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 2010;10:490-500.
162. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25high regulatory cells in human peripheral blood. J Immunol 2001;167:1245-1253.
163. Liu W, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 2006;203:1701-1711.
164. Allan SE, et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol 2007;19:345-354.
165. Seddiki N, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med 2006;203:1693-1700.
166. Aerts NE, Dombrecht EJ, Ebo DG, Bridts CH, Stevens WJ, De Clerck LS. Activated T cells complicate the identification of regulatory T cells in rheumatoid arthritis. Cell Immunol 2008;251:109-115.
167. Miyara M, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009;30:899-911.
168. Del Pozo-Balado Mdel M, Leal M, Mendez-Lagares G, Pacheco YM. CD4(+)CD25(+/hi)CD127(lo) phenotype does not accurately identify regulatory T cells in all populations of HIV-infected persons. J Infect Dis 2010;201:331-335.
169. Ermann J, et al. Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD. Blood 2005;105:2220-2226.
170. McFarland RD, Douek DC, Koup RA, Picker LJ. Identification of a human recent thymic emigrant phenotype. Proc Natl Acad Sci USA 2000;97:4215-4220.
171. Annunziato F, et al. Phenotype, localization, and mechanism of suppression of CD4(+)CD25(+) human thymocytes. J Exp Med 2002;196:379-387.
172. Jago CB, Yates J, Camara NO, Lechler RI, Lombardi G. Differential expression of CTLA-4 among T cell subsets. Clin Exp Immunol 2004;136:463-471.
173. Baecher-Allan C, Wolf E, Hafler DA. MHC class II expression identifies functionally distinct human regulatory T cells. J Immunol 2006;176:4622-4631.
174. Putnam AL, et al. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes 2009;58:652-662.
175. Tran DQ, Andersson J, Wang R, Ramsey H, Unutmaz D, Shevach EM. GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells. Proc Natl Acad Sci USA 2009;106:13445-13450.
176. Wang R, Wan Q, Kozhaya L, Fujii H, Unutmaz D. Identification of a regulatory T cell specific cell surface molecule that mediates suppressive signals and induces Foxp3 expression. PLoS ONE 2008;3:e2705.
177. Probst-Kepper M, et al. GARP: a key receptor controlling FOXP3 in human regulatory T cells. J Cell Mol Med 2009;13:3343-3357.
178. Wang R, Kozhaya L, Mercer F, Khaitan A, Fujii H, Unutmaz D. Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells. Proc Natl Acad Sci USA 2009;106:13439-13444.
179. Liu G, et al. The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR. Nat Immunol 2009;10:769-777.
180. Jeffery LE, et al. 1, 25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol 2009;183:5458-5467.
181. Strober W. Vitamin A rewrites the ABCs of oral tolerance. Mucosal Immunol 2008;1:92-95.
182. Kishimoto T. IL-6: from its discovery to clinical applications. Int Immunol 2010;22:347-352.
183. Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2003;299:1033-1036.
184. Bettelli E, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441:235-238.
185. Ji N, et al. Direct catalytic conversion of cellulose into ethylene glycol using nickel-promoted tungsten carbide catalysts. Angew Chem Int Ed Engl 2008;47:8510-8513.
186. Goodman WA, Levine AD, Massari JV, Sugiyama H, McCormick TS, Cooper KD. IL-6 signaling in psoriasis prevents immune suppression by regulatory T cells. J Immunol 2009;183:3170-3176.
187. Goodman WA, Young AB, McCormick TS, Cooper KD, Levine AD. Stat3 phosphorylation mediates resistance of primary human T cells to regulatory T cell suppression. J Immunol 2011;186:3336-3345.
188. Nyirenda MH, et al. TLR2 stimulation drives human naive and effector regulatory T cells into a Th17-like phenotype with reduced suppressive function. J Immunol 2011;187:2278-2290.
189. Chen X, Baumel M, Mannel DN, Howard OM, Oppenheim JJ. Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+CD25+ T regulatory cells. J Immunol 2007;179:154-161.
190. Chen X, Wu X, Zhou Q, Howard OM, Netea MG, Oppenheim JJ. TNFR2 is critical for the stabilization of the CD4+Foxp3+ regulatory T. cell phenotype in the inflammatory environment. J Immunol 2013;190:1076-1084.
191. van Mierlo GJ, et al. Cutting edge: TNFR-shedding by CD4+CD25+ regulatory T cells inhibits the induction of inflammatory mediators. J Immunol 2008;180:2747-2751.
192. Moreland LW, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 1997;337:141-147.
193. Valencia X, Stephens G, Goldbach-Mansky R, Wilson M, Shevach EM, Lipsky PE. TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood 2006;108:253-261.
194. Perez-Alvarez R, Perez-de-Lis M, Ramos-Casals M. Biologics-induced autoimmune diseases. Curr Opin Rheumatol 2013;25:56-64.
195. Oldenhove G, et al. Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 2009;31:772-786.
196. Deknuydt F, Bioley G, Valmori D, Ayyoub M. IL-1beta and IL-2 convert human Treg into T(H)17 cells. Clin Immunol 2009;131:298-307.
197. Izcue A, et al. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 2008;28:559-570.
198. Hsieh CS, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 2004;21:267-277.
199. Deaglio S, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007;204:1257-1265.
200. Alam MS, et al. CD73 is expressed by human regulatory T helper cells and suppresses proinflammatory cytokine production and Helicobacter felis-induced gastritis in mice. J Infect Dis 2009;199:494-504.
201. Kleinewietfeld M, et al. CD49d provides access to "untouched" human Foxp3+ Treg free of contaminating effector cells. Blood 2009;113:827-836.
202. Chen X, Subleski JJ, Hamano R, Howard OM, Wiltrout RH, Oppenheim JJ. Co-expression of TNFR2 and CD25 identifies more of the functional CD4+FOXP3+ regulatory T cells in human peripheral blood. Eur J Immunol 2010;40:1099-1106.
203. Tran DQ, Andersson J, Hardwick D, Bebris L, Illei GG, Shevach EM. Selective expression of latency-associated peptide (LAP) and IL-1 receptor type I/II (CD121a/CD121b) on activated human FOXP3+ regulatory T cells allows for their purification from expansion cultures. Blood 2009;113:5125-5133.
204. Getnet D, et al. A role for the transcription factor Helios in human CD4(+)CD25(+) regulatory T cells. Mol Immunol 2010;47:1595-1600.
205. Thornton AM, et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol 2010;184:3433-3441.
206. 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.