Regulatory T cells in autoimmune neuroinflammation

Immunological Reviews

Volumn 259, Issue 1, 2014, Pages 231-244

  Kleinewietfeld, Markus ^a,b,c   Hafler, David A ^a,b  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b BROAD INSTITUTE OF MIT AND HARVARD   (United States)

^c DRESDEN UNIVERSITY OF TECHNOLOGY   (Germany)

Author keywords

Autoimmunity; FoxP3; Multiple sclerosis; Regulatory T cells; Tr1; Treg

Indexed keywords

INTERLEUKIN 10; TRANSCRIPTION FACTOR FOXP3;

ARTICLE; CD4+ T LYMPHOCYTE; CELL LINEAGE; HELPER CELL; HUMAN; MULTIPLE SCLEROSIS; NERVOUS SYSTEM INFLAMMATION; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN POLYMORPHISM; REGULATORY T LYMPHOCYTE;

AUTOIMMUNITY; FOXP3; MULTIPLE SCLEROSIS; REGULATORY T CELLS; TR1; TREG;

ANIMALS; AUTOIMMUNE DISEASES; FORKHEAD TRANSCRIPTION FACTORS; HUMANS; MULTIPLE SCLEROSIS; NEUROGENIC INFLAMMATION; T-LYMPHOCYTE SUBSETS; T-LYMPHOCYTES, REGULATORY;

EID: 84897935033     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/imr.12169     Document Type: Article

References (166)

1. Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FoxP3+ regulatory T cells in the human immune system. Nat Rev Immunol 2010;10:490-500.
2. Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 2006;212:28-50.
3. Chaudhry A, Rudensky AY. Control of inflammation by integration of environmental cues by regulatory T cells. J Clin Invest 2013;123:939-944.
4. Nylander A, Hafler DA. Multiple sclerosis. J Clin Invest 2012;122:1180-1188.
5. 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.
6. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25high regulatory cells in human peripheral blood. J Immunol 2001;167:1245-1253.
7. Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH. Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med 2001;193:1285-1294.
8. Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G. Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med 2001;193:1303-1310.
9. Levings MK, Sangregorio R, Roncarolo MG. Human cd25(+)cd4(+) t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med 2001;193:1295-1302.
10. Ng WF, et al. Human CD4(+)CD25(+) cells: a naturally occurring population of regulatory T cells. Blood 2001;98:2736-2744.
11. Stephens LA, Mottet C, Mason D, Powrie F. Human CD4(+)CD25(+) thymocytes and peripheral T cells have immune suppressive activity in vitro. Eur J Immunol 2001;31:1247-1254.
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, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330-336.
14. 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.
15. Randolph DA, Fathman CG. Cd4+Cd25+ regulatory T cells and their therapeutic potential. Annu Rev Med 2006;57:381-402.
16. 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.
17. 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.
18. 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.
19. Sakaguchi S, et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 2006;212:8-27.
20. Hsieh CS, Lee HM, Lio CW. Selection of regulatory T cells in the thymus. Nat Rev Immunol 2012;12:157-167.
21. Klein L, Jovanovic K. Regulatory T cell lineage commitment in the thymus. Semin Immunol 2011;23:401-409.
22. Floess S, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 2007;5:e38.
23. Huehn J, Polansky JK, Hamann A. Epigenetic control of FoxP3 expression: the key to a stable regulatory T-cell lineage? Nat Rev Immunol 2009;9:83-89.
24. Curotto de Lafaille MA, Lafaille JJ. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 2009;30:626-635.
25. 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.
26. 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.
27. Shevach EM, Tran DQ, Davidson TS, Andersson J. The critical contribution of TGF-beta to the induction of Foxp3 expression and regulatory T cell function. Eur J Immunol 2008;38:915-917.
28. Allan SE, Song-Zhao GX, Abraham T, McMurchy AN, Levings MK. Inducible reprogramming of human T cells into Treg cells by a conditionally active form of FoxP3. Eur J Immunol 2008;38:3282-3289.
29. Allan SE, et al. Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FoxP3. Mol Ther 2008;16:194-202.
30. Yadav M, Stephan S, Bluestone JA. Peripherally induced tregs - role in immune homeostasis and autoimmunity. Front Immunol 2013;4:232.
31. Lu L, Zhou X, Wang J, Zheng SG, Horwitz DA. Characterization of protective human CD4CD25 FoxP3 regulatory T cells generated with IL-2. TGF-beta and retinoic acid. PLoS ONE 2010;5:e15150.
32. Vukmanovic-Stejic M, et al. Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo. J Clin Invest 2006;116:2423-2433.
33. 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.
34. 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.
35. Kleinewietfeld M, et al. CD49d provides access to "untouched" human Foxp3+ Treg free of contaminating effector cells. Blood 2009;113:827-836.
36. Miyara M, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009;30:899-911.
37. Hoffmann P, et al. Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. Blood 2006;108:4260-4267.
38. Kimmig S, et al. Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood. J Exp Med 2002;195:789-794.
39. Valmori D, Merlo A, Souleimanian NE, Hesdorffer CS, Ayyoub M. A peripheral circulating compartment of natural naive CD4 Tregs. J Clin Invest 2005;115:1953-1962.
40. 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.
41. Ito T, et al. Two functional subsets of FoxP3+ regulatory T cells in human thymus and periphery. Immunity 2008;28:870-880.
42. Baecher-Allan C, Wolf E, Hafler DA. MHC class II expression identifies functionally distinct human regulatory T cells. J Immunol 2006;176:4622-4631.
43. Baecher-Allan CM, et al. CD2 costimulation reveals defective activity by human CD4+CD25(hi) regulatory cells in patients with multiple sclerosis. J Immunol 2011;186:3317-3326.
44. Kleinewietfeld M, Puentes F, Borsellino G, Battistini L, Rotzschke O, Falk K. CCR6 expression defines regulatory effector/memory-like cells within the CD25(+)CD4+ T-cell subset. Blood 2005;105:2877-2886.
45. Kitamura K, Farber JM, Kelsall BL. CCR6 marks regulatory T cells as a colon-tropic, IL-10-producing phenotype. J Immunol 2010;185:3295-3304.
46. Waldron-Lynch F, et al. Teplizumab induces human gut-tropic regulatory cells in humanized mice and patients. Sci Transl Med 2012;4:118ra112.
47. Yamazaki T, et al. CCR6 regulates the migration of inflammatory and regulatory T cells. J Immunol 2008;181:8391-8401.
48. Munn DH, et al. Potential regulatory function of human dendritic cells expressing indoleamine 2, 3-dioxygenase. Science 2002;297:1867-1870.
49. Fallarino F, et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 2003;4:1206-1212.
50. Fritzsching B, et al. Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death. Blood 2006;108:3371-3378.
51. Vahedi G, et al. Helper T-cell identity and evolution of differential transcriptomes and epigenomes. Immunol Rev 2013;252:24-40.
52. Kleinewietfeld M, Hafler DA. The plasticity of human Treg and Th17 cells and its role in autoimmunity. Semin Immunol 2013;25:305-312.
53. Apostolou I, von Boehmer H. In vivo instruction of suppressor commitment in naive T cells. J Exp Med 2004;199:1401-1408.
54. Rosenblum MD, Gratz IK, Paw JS, Lee K, Marshak-Rothstein A, Abbas AK. Response to self antigen imprints regulatory memory in tissues. Nature 2011;480:538-542.
55. Gratz IK, Rosenblum MD, Abbas AK. The life of regulatory T cells. Ann NY Acad Sci 2013;1283:8-12.
56. Gratz IK, et al. Cutting edge: memory regulatory t cells require IL-7 and not IL-2 for their maintenance in peripheral tissues. J Immunol 2013;190:4483-4487.
57. Vignali DAA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol 2008;8:523-532.
58. Strauss L, Bergmann C, Whiteside TL. Human circulating CD4+CD25highFoxp3+ regulatory T cells kill autologous CD8+ but not CD4+ responder cells by Fas-mediated apoptosis. J Immunol 2009;182:1469-1480.
59. Wing K, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008;322:271-275.
60. Qureshi OS, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 2011;332:600-603.
61. Munn DH, Sharma MD, Mellor AL. Ligation of B7-1/B7-2 by human CD4+ T cells triggers indoleamine 2, 3-dioxygenase activity in dendritic cells. J Immunol 2004;172:4100-4110.
62. Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 2004;4:762-774.
63. Munn DH, et al. Expression of indoleamine 2, 3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest 2004;114:280-290.
64. Grossman WJ, Verbsky JW, Barchet W, Colonna M, Atkinson JP, Ley TJ. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 2004;21:589-601.
65. de la Rosa M, Rutz S, Dorninger H, Scheffold A. Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur J Immunol 2004;34:2480-2488.
66. Busse D, et al. Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments. Proc Natl Acad Sci USA 2010;107:3058-3063.
67. Borsellino G, et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 2007;110:1225-1232.
68. 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.
69. Dwyer KM, et al. Expression of CD39 by human peripheral blood CD4+ CD25+ T cells denotes a regulatory memory phenotype. Am J Transplant 2010;10:2410-2420.
70. Doherty GA, et al. CD73 is a phenotypic marker of effector memory Th17 cells in inflammatory bowel disease. Eur J Immunol 2012;42:3062-3072.
71. Dieckmann D, Bruett CH, Ploettner H, Lutz MB, Schuler G. Human CD4(+)CD25(+) regulatory, contact-dependent T cells induce interleukin 10-producing, contact-independent type 1-like regulatory T cells. J Exp Med 2002;196:247-253.
72. Jonuleit H, Schmitt E, Kakirman H, Stassen M, Knop J, Enk AH. Infectious tolerance: human CD25(+) regulatory T cells convey suppressor activity to conventional CD4(+) T helper cells. J Exp Med 2002;196:255-260.
73. Gregori S, Goudy KS, Roncarolo MG. The cellular and molecular mechanisms of immuno-suppression by human type 1 regulatory T cells. Front Immunol 2012;3:30.
74. Bacchetta R, et al. High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. J Exp Med 1994;179:493-502.
75. Bacchetta R, Sartirana C, Levings MK, Bordignon C, Narula S, Roncarolo MG. Growth and expansion of human T regulatory type 1 cells are independent from TCR activation but require exogenous cytokines. Eur J Immunol 2002;32:2237-2245.
76. Groux H, et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997;389:737-742.
77. Levings MK, Sangregorio R, Galbiati F, Squadrone S, de Waal Malefyt R, Roncarolo MG. IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol 2001;166:5530-5539.
78. Barrat FJ, et al. In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med 2002;195:603-616.
79. Battaglia M, et al. Rapamycin and interleukin-10 treatment induces T regulatory type 1 cells that mediate antigen-specific transplantation tolerance. Diabetes 2006;55:40-49.
80. Astier A, Trescol-Biemont MC, Azocar O, Lamouille B, Rabourdin-Combe C. Cutting edge: CD46, a new costimulatory molecule for T cells, that induces p120CBL and LAT phosphorylation. J Immunol 2000;164:6091-6095.
81. Kemper C, Chan AC, Green JM, Brett KA, Murphy KM, Atkinson JP. Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature 2003;421:388-392.
82. Wakkach A, Cottrez F, Groux H. Differentiation of regulatory T cells 1 is induced by CD2 costimulation. J Immunol 2001;167:3107-3113.
83. Awasthi A, et al. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol 2007;8:1380-1389.
84. Pot C, Apetoh L, Awasthi A, Kuchroo VK. Induction of regulatory Tr1 cells and inhibition of T(H)17 cells by IL-27. Semin Immunol 2011;23:438-445.
85. Pot C, Apetoh L, Kuchroo VK. Type 1 regulatory T cells (Tr1) in autoimmunity. Semin Immunol 2011;23:202-208.
86. Iwasaki Y, et al. Egr-2 transcription factor is required for Blimp-1-mediated IL-10 production in IL-27-stimulated CD4+ T cells. Eur J Immunol 2013;43:1063-1073.
87. Grossman WJ, Verbsky JW, Tollefsen BL, Kemper C, Atkinson JP, Ley TJ. Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells. Blood 2004;104:2840-2848.
88. Magnani CF, et al. Killing of myeloid APCs via HLA class I, CD2 and CD226 defines a novel mechanism of suppression by human Tr1 cells. Eur J Immunol 2011;41:1652-1662.
89. Mandapathil M, et al. Adenosine and prostaglandin E2 cooperate in the suppression of immune responses mediated by adaptive regulatory T cells. J Biol Chem 2010;285:27571-27580.
90. Gagliani N, et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med 2013;19:739-746.
91. Hafler DA. Multiple sclerosis. J Clin Invest 2004;113:788-794.
92. Sawcer S, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011;476:214-219.
93. Beecham AH, et al. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 2013;45:1353-1360.
94. Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Eng J Med 2002;347:911-920.
95. Willer CJ, Dyment DA, Risch NJ, Sadovnick AD, Ebers GC. Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci USA 2003;100:12877-12882.
96. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: noninfectious factors. Ann Neurol 2007;61:504-513.
97. Ascherio A, Munger KL, Lunemann JD. The initiation and prevention of multiple sclerosis. Nat Rev Immunol 2012;8:602-612.
98. Raddassi K, et al. Increased frequencies of myelin oligodendrocyte glycoprotein/MHC class II-binding CD4 cells in patients with multiple sclerosis. J Immunol 2011;187:1039-1046.
99. Lowther DE, Hafler DA. Regulatory T cells in the central nervous system. Immunol Rev 2012;248:156-169.
100. Putheti P, Soderstrom M, Link H, Huang YM. Effect of glatiramer acetate (Copaxone) on CD4+CD25high T regulatory cells and their IL-10 production in multiple sclerosis. J Neuroimmunol 2003;144:125-131.
101. 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.
102. 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.
103. 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.
104. 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.
105. Kumar M, et al. CD4+CD25+FoxP3+ T lymphocytes fail to suppress myelin basic protein-induced proliferation in patients with multiple sclerosis. J Neuroimmunol 2006;180:178-184.
106. Venken K, et al. Secondary progressive in contrast to relapsing-remitting multiple sclerosis patients show a normal CD4+CD25+ regulatory T-cell function and FoxP3 expression. J Neurosci Res 2006;83:1432-1446.
107. Venken K, Hellings N, Broekmans T, Hensen K, Rummens JL, Stinissen P. Natural naive CD4+CD25+CD127low regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: Recovery of memory Treg homeostasis during disease progression. J Immunol 2008;180:6411-6420.
108. Frisullo G, et al. Regulatory T cells fail to suppress CD4T+-bet+ T cells in relapsing multiple sclerosis patients. Immunology 2009;127:418-428.
109. Huan J, et al. Decreased FoxP3 levels in multiple sclerosis patients. J Neurosci Res 2005;81:45-52.
110. Sellebjerg F, Krakauer M, Khademi M, Olsson T, Sorensen PS. FoxP3, CBLB and ITCH gene expression and cytotoxic T lymphocyte antigen 4 expression on CD4(+) CD25(high) T cells in multiple sclerosis. Clin Exp Immunol 2012;170:149-155.
111. Venken K, Hellings N, Liblau R, Stinissen P. Disturbed regulatory T cell homeostasis in multiple sclerosis. Trends Mol Med 2010;16:58-68.
112. de Andres C, et al. Interferon beta-1a therapy enhances CD4+ regulatory T-cell function: An ex vivo and in vitro longitudinal study in relapsing-remitting multiple sclerosis. J Neuroimmunol 2007;182:204-211.
113. Haas J, Korporal M, Balint B, Fritzsching B, Schwarz A, Wildemann B. Glatiramer acetate improves regulatory T-cell function by expansion of naive CD4(+)CD25(+)FoxP3(+)CD31(+) T-cells in patients with multiple sclerosis. J Neuroimmunol 2009;216:113-117.
114. Chiarini M, et al. Modulation of the central memory and Tr1-like regulatory T cells in multiple sclerosis patients responsive to interferon-beta therapy. Mult Scler 2012;18:788-798.
115. Korporal M, et al. Interferon beta-induced restoration of regulatory T-cell function in multiple sclerosis is prompted by an increase in newly generated naive regulatory T cells. Arch Neurol 2008;65:1434-1439.
116. Stenner MP, et al. Effects of natalizumab treatment on Foxp3+ T regulatory cells. PLoS ONE 2008;3:e3319.
117. Putzki N, Baranwal MK, Tettenborn B, Limmroth V, Kreuzfelder E. Effects of natalizumab on circulating B cells, T regulatory cells and natural killer cells. Eur Neurol 2010;63:311-317.
118. Kinnunen T, et al. Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells. Blood 2013;121:1595-1603.
119. Kinnunen T, et al. Specific peripheral B cell tolerance defects in patients with multiple sclerosis. J Clin Invest 2013;123:2737-2741.
120. Schmidt A, et al. Human regulatory T cells rapidly suppress T cell receptor-induced Ca(2+), NF-kappaB, and NFAT signaling in conventional T cells. Sci Signal 2011;4:ra90.
121. Schwarz A, et al. Fine-tuning of regulatory T cell function: The role of calcium signals and naive regulatory T cells for regulatory T cell deficiency in multiple sclerosis. J Immunol 2013;190:4965-4970.
122. Fletcher JM, et al. CD39+Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol 2009;183:7602-7610.
123. Niemela J, Ifergan I, Yegutkin GG, Jalkanen S, Prat A, Airas L. IFN-beta regulates CD73 and adenosine expression at the blood-brain barrier. Eur J Immunol 2008;38:2718-2726.
124. Mariathasan S, Monack DM. Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol 2007;7:31-40.
125. Schnurr M, Toy T, Shin A, Wagner M, Cebon J, Maraskovsky E. Extracellular nucleotide signaling by P2 receptors inhibits IL-12 and enhances IL-23 expression in human dendritic cells: a novel role for the cAMP pathway. Blood 2005;105:1582-1589.
126. Kleinewietfeld M, et al. Hydrolysis of extracellular ATP by CD39(+) Treg cells: context matters! Blood 2008;111:965-966.
127. Dominguez-Villar M, Baecher-Allan CM, Hafler DA. Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. Nat Med 2011;17:673-675.
128. Baecher-Allan C, Hafler DA. Human regulatory T cells and their role in autoimmune disease. Immunol Rev 2006;212:203-216.
129. Brusko TM, Putnam AL, Bluestone JA. Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. Immunol Rev 2008;223:371-390.
130. McClymont SA, et al. Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J Immunol 2011;186:3918-3926.
131. Beriou G, et al. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood 2009;113:4240-4249.
132. Longhi MS, et al. Inhibition of interleukin-17 promotes differentiation of CD25(-) cells into stable T regulatory cells in patients with autoimmune hepatitis. Gastroenterology 2012;142:1526-1535, e1526.
133. Muratori L, Longhi MS. The interplay between regulatory and effector T cells in autoimmune hepatitis: implications for innovative treatment strategies. J Autoimmun 2013;46:74-80.
134. Liu X, et al. Elevated levels of CD4(+)CD25(+)FoxP3(+) T cells in systemic sclerosis patients contribute to the secretion of IL-17 and immunosuppression dysfunction. PLoS ONE 2013;8:e64531.
135. Bovenschen HJ, van de Kerkhof PC, van Erp PE, Woestenenk R, Joosten I, Koenen HJ. Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. J Invest Dermatol 2011;131:1853-1860.
136. Singh K, et al. Reduced CD18 levels drive regulatory T cell conversion into Th17 cells in the CD18hypo PL/J mouse model of psoriasis. J Immunol 2013;190:2544-2553.
137. Hafler DA, et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007;357:851-862.
138. De Jager PL, et al. The role of the CD58 locus in multiple sclerosis. Proc Natl Acad Sci USA 2009;106:5264-5269.
139. Roychoudhuri R, et al. BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis. Nature 2013;498:506-510.
140. Smolders J, et al. Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis. PLoS ONE 2009;4:e6635.
141. Nutsch KM, Hsieh CS. T cell tolerance and immunity to commensal bacteria. Curr Opin Immunol 2012;24:385-391.
142. Nagano Y, Itoh K, Honda K. The induction of Treg cells by gut-indigenous Clostridium. Curr Opin Immunol 2012;24:392-397.
143. Collins SM, Surette M, Bercik P. The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 2012;10:735-742.
144. Ochoa-Reparaz J, Mielcarz DW, Begum-Haque S, Kasper LH. Gut, bugs, and brain: role of commensal bacteria in the control of central nervous system disease. Ann Neurol 2011;69:240-247.
145. Atarashi K, Honda K. Microbiota in autoimmunity and tolerance. Curr Opin Immunol 2011;23:761-768.
146. Littman DR, Rudensky AY. Th17 and regulatory T cells in mediating and restraining inflammation. Cell 2010;140:845-858.
147. Kleinewietfeld M, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 2013;496:518-522.
148. Wu C, et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 2013;496:513-517.
149. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001;19:683-765.
150. Astier AL, Hafler DA. Abnormal Tr1 differentiation in multiple sclerosis. J Neuroimmunol 2007;191:70-78.
151. Adorini L. Immunomodulatory effects of vitamin D receptor ligands in autoimmune diseases. Int Immunopharmacol 2002;2:1017-1028.
152. Spach KM, Nashold FE, Dittel BN, Hayes CE. IL-10 signaling is essential for 1, 25-dihydroxyvitamin D3-mediated inhibition of experimental autoimmune encephalomyelitis. J Immunol 2006;177:6030-6037.
153. Simon KC, Munger KL, Ascherio A. Vitamin D and multiple sclerosis: epidemiology, immunology, and genetics. Curr Opin Neurol 2012;25:246-251.
154. 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.
155. Marie JC, Astier AL, Rivailler P, Rabourdin-Combe C, Wild TF, Horvat B. Linking innate and acquired immunity: divergent role of CD46 cytoplasmic domains in T cell induced inflammation. Nat Immunol 2002;3:659-666.
156. Ni Choileain S, Weyand NJ, Neumann C, Thomas J, So M, Astier AL. The dynamic processing of CD46 intracellular domains provides a molecular rheostat for T cell activation. PLoS ONE 2011;6:e16287.
157. Martinez-Forero I, et al. IL-10 suppressor activity and ex vivo Tr1 cell function are impaired in multiple sclerosis. Eur J Immunol 2008;38:576-586.
158. Ma A, et al. Dysfunction of IL-10-producing type 1 regulatory T cells and CD4(+)CD25(+) regulatory T cells in a mimic model of human multiple sclerosis in Cynomolgus monkeys. Int Immunopharmacol 2009;9:599-608.
159. Kickler K, Ni Choileain S, Williams A, Richards A, Astier AL. Calcitriol modulates the CD46 pathway in T cells. PLoS ONE 2012;7:e48486.
160. Mascanfroni ID, et al. IL-27 acts on DCs to suppress the T cell response and autoimmunity by inducing expression of the immunoregulatory molecule CD39. Nat Immunol 2013;14:1054-1063.
161. Apetoh L, et al. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat Immunol 2010;11:854-861.
162. Pot C, et al. Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J Immunol 2009;183:797-801.
163. Wang H, et al. IL-27 induces the differentiation of Tr1-like cells from human naive CD4+ T cells via the phosphorylation of STAT1 and STAT3. Immunol Lett 2011;136:21-28.
164. Murugaiyan G, Mittal A, Lopez-Diego R, Maier LM, Anderson DE, Weiner HL. IL-27 is a key regulator of IL-10 and IL-17 production by human CD4+ T cells. J Immunol 2009;183:2435-2443.
165. Sweeney CM, et al. IL-27 mediates the response to IFN-beta therapy in multiple sclerosis patients by inhibiting Th17 cells. Brain Behav Immun 2011;25:1170-1181.
166. Zhang X, Jin J, Tang Y, Speer D, Sujkowska D, Markovic-Plese S. IFN-beta1a inhibits the secretion of Th17-polarizing cytokines in human dendritic cells via TLR7 up-regulation. J Immunol 2009;182:3928-3936.