Interplay Between Effector Th17 and Regulatory T Cells

  • Amit Awasthi
  • Gopal Murugaiyan
  • Vijay K. Kuchroo
Article

Abstract

Introduction

Over two decades ago, T helper cells were classified into its functional subsets. Soon after the classical observation of Mosmann et al., immunologists agreed to accept the Th1/Th2 paradigm of the T helper subsets. Each subset is not only characterized by its specific cytokines pattern and effector functions but also by their properties to counter regulate each other’s functions. This classification helped to understand the complex principles of T helper cell biology and allowed us to comprehend different immune reactions in context of Th1 and Th2 subsets.

Discussion

Although Th1 subsets thought to be the crucial player for most of the organ-specific autoimmune diseases like multiple sclerosis and type-1 diabetes but the loss of Th1 dominant cytokine, IFN-γ did not prevent the development of autoimmunity which raised the possibility of involvement of other Th subsets, different from Th1 cells in the induction of autoimmunity.

Conclusion

Recently, a new subset of Th cells that predominantly produce IL-17 and induce autoimmunity has been discovered, and it is believed that this subset may be the major cell type involved in orchestrating tissue inflammation and autoimmunity. Recent data propose that the differentiation factors of Th17 cells reveal a link with induction of Foxp3+ regulatory T cells. Here, we review the interplay between Th17 and Foxp3+ T-reg cells and Tr1 cells during autoimmune inflammatory reaction.

Keywords

Inflammation T helper cells regulatory T cells autoimmunity Th17 cells 

Abbreviations

Th

T helper

IL

Interleukin

IFN-γ

Interferon gamma

TGF-β

Transforming growth factor beta

Tr1

T-regulatory cells type-1

T-regs

Regulatory T cells

EAE

experimental autoimmune encephalomyelitis

MS

Multiple sclerosis

CIA

Collagen induced arthritis

CNS

Central nervous system

STAT

Signal transducers and activators of transcription

MAPK

Mitogen activated protein kinases

References

  1. 1.
    Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145.PubMedCrossRefGoogle Scholar
  2. 2.
    Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of T(H)17 cells. Nature 2008;453:1051.PubMedCrossRefGoogle Scholar
  3. 3.
    Murray HW, Spitalny GL, Nathan CF. Activation of mouse peritoneal macrophages in vitro and in vivo by interferon-gamma. J Immunol. 1985;134:1619.PubMedGoogle Scholar
  4. 4.
    Kuchroo VK, Anderson AC, Waldner H, Munder M, Bettelli E, Nicholson LB. T cell response in experimental autoimmune encephalomyelitis (EAE): role of self and cross-reactive antigens in shaping, tuning, and regulating the autopathogenic T cell repertoire. Annu Rev Immunol. 2002;20:101.PubMedCrossRefGoogle Scholar
  5. 5.
    Ansel KM, Djuretic I, Tanasa B, Rao A. Regulation of Th2 differentiation and Il4 locus accessibility. Annu Rev Immunol. 2006;24:607.PubMedCrossRefGoogle Scholar
  6. 6.
    Anthony RM, Rutitzky LI, Urban JF Jr, Stadecker MJ, Gause WC. Protective immune mechanisms in helminth infection. Nat Rev Immunol. 2007;7:975.PubMedCrossRefGoogle Scholar
  7. 7.
    Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 2000;100:655.PubMedCrossRefGoogle Scholar
  8. 8.
    Mullen AC, High FA, Hutchins AS, Lee HW, Villarino AV, Livingston DM, Kung AL, Cereb N, Yao TP, Yang SY, Reiner SL. Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 2001;292:1907.PubMedCrossRefGoogle Scholar
  9. 9.
    Ben-Nun A, Cohen IR. Vaccination against autoimmune encephalomyelitis (EAE): attenuated autoimmune T lymphocytes confer resistance to induction of active EAE but not to EAE mediated by the intact T lymphocyte line. Eur J Immunol. 1981;11:949.PubMedCrossRefGoogle Scholar
  10. 10.
    Pettinelli CB, McFarlin DE. Adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice after in vitro activation of lymph node cells by myelin basic protein: requirement for Lyt 1+ 2-T lymphocytes. J Immunol. 1981;127:1420.PubMedGoogle Scholar
  11. 11.
    Ferber IA, Brocke S, Taylor-Edwards C, Ridgway W, Dinisco C, Steinman L, Dalton D, Fathman CG. Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol. 1996;156:5.PubMedGoogle Scholar
  12. 12.
    Matthys P, Vermeire K, Mitera T, Heremans H, Huang S, Billiau A. Anti-IL-12 antibody prevents the development and progression of collagen-induced arthritis in IFN-gamma receptor-deficient mice. Eur J Immunol. 1998;28:2143.PubMedCrossRefGoogle Scholar
  13. 13.
    Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003;421:744.PubMedCrossRefGoogle Scholar
  14. 14.
    Gran B, Zhang GX, Yu S, Li J, Chen XH, Ventura ES, Kamoun M, Rostami A. IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J Immunol. 2002;169:7104.PubMedGoogle Scholar
  15. 15.
    Becher B, Durell BG, Noelle RJ. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J Clin Invest. 2002;110:493.PubMedGoogle Scholar
  16. 16.
    Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000;13:715.PubMedCrossRefGoogle Scholar
  17. 17.
    Afkarian M, Sedy JR, Yang J, Jacobson NG, Cereb N, Yang SY, Murphy TL, Murphy KM. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nat Immunol. 2002;3:549.PubMedCrossRefGoogle Scholar
  18. 18.
    Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem. 2003;278:1910.PubMedCrossRefGoogle Scholar
  19. 19.
    Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201:233.PubMedCrossRefGoogle Scholar
  20. 20.
    Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441:235.PubMedCrossRefGoogle Scholar
  21. 21.
    Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24:179.PubMedCrossRefGoogle Scholar
  22. 22.
    Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 2006;126:1121.PubMedCrossRefGoogle Scholar
  23. 23.
    Veldhoen M, Hocking RJ, Flavell RA, Stockinger B. Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat Immunol. 2006;7:1151.PubMedCrossRefGoogle Scholar
  24. 24.
    Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, Schluns K, Tian Q, Watowich SS, Jetten AM, Dong C. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 2007;448:480.PubMedCrossRefGoogle Scholar
  25. 25.
    Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 2007;448:484.PubMedCrossRefGoogle Scholar
  26. 26.
    Kaplan MH, Grusby MJ. Regulation of T helper cell differentiation by STAT molecules. J Leukoc Biol. 1998;64:2.PubMedGoogle Scholar
  27. 27.
    Takeda A, Hamano S, Yamanaka A, Hanada T, Ishibashi T, Mak TW, Yoshimura A, Yoshida H. Cutting edge: role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Th1 commitment. J Immunol. 2003;170:4886.PubMedGoogle Scholar
  28. 28.
    Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S, Nakanishi K, Yoshida N, Kishimoto T, Akira S. Essential role of Stat6 in IL-4 signalling. Nature 1996;380:627.PubMedCrossRefGoogle Scholar
  29. 29.
    Kaplan MH, Schindler U, Smiley ST, Grusby MJ. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 1996;4:313.PubMedCrossRefGoogle Scholar
  30. 30.
    Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 1997;89:587.PubMedCrossRefGoogle Scholar
  31. 31.
    Mathur AN, Chang HC, Zisoulis DG, Stritesky GL, Yu Q, O’Malley JT, Kapur R, Levy DE, Kansas GS, Kaplan MH. Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol. 2007;178:4901.PubMedGoogle Scholar
  32. 32.
    Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS, Watowich SS, Tian Q, Jetten AM, Dong C. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 2008;28:29.PubMedCrossRefGoogle Scholar
  33. 33.
    Aggarwal S, Gurney AL. IL-17: prototype member of an emerging cytokine family. J Leukoc Biol. 2002;71:1.PubMedGoogle Scholar
  34. 34.
    Moseley TA, Haudenschild DR, Rose L, Reddi AH. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 2003;14:155.PubMedCrossRefGoogle Scholar
  35. 35.
    Rouvier E, Luciani MF, Mattei MG, Denizot F, Golstein P. CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J Immunol. 1993;150:5445.PubMedGoogle Scholar
  36. 36.
    Maitra A, Shen F, Hanel W, Mossman K, Tocker J, Swart D, Gaffen SL. Distinct functional motifs within the IL-17 receptor regulate signal transduction and target gene expression. Proc Natl Acad Sci USA. 2007;104:7506.PubMedCrossRefGoogle Scholar
  37. 37.
    Huang F, Kao CY, Wachi S, Thai P, Ryu J, Wu R. Requirement for both JAK-mediated PI3K signaling and ACT1/TRAF6/TAK1-dependent NF-kappaB activation by IL-17A in enhancing cytokine expression in human airway epithelial cells. J Immunol. 2007;179:6504.PubMedGoogle Scholar
  38. 38.
    Hwang SY, Kim JY, Kim KW, Park MK, Moon Y, Kim WU, Kim HY. IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kappaB-and PI3-kinase/Akt-dependent pathways. Arthritis Res Ther. 2004;6:R120.PubMedCrossRefGoogle Scholar
  39. 39.
    Rangachari M, Mauermann N, Marty RR, Dirnhofer S, Kurrer MO, Komnenovic V, Penninger JM, Eriksson U. T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17. J Exp Med. 2006;203:2009.PubMedCrossRefGoogle Scholar
  40. 40.
    Pflanz S, Timans JC, Cheung J, Rosales R, Kanzler H, Gilbert J, Hibbert L, Churakova T, Travis M, Vaisberg E, Blumenschein WM, Mattson JD, Wagner JL, To W, Zurawski S, McClanahan TK, Gorman DM, Bazan JF, de Waal Malefyt R, Rennick D, Kastelein RA. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells. Immunity 2002;16:779.PubMedCrossRefGoogle Scholar
  41. 41.
    Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM, Johnson LM, Villarino AV, Huang Q, Yoshimura A, Sehy D, Saris CJ, O’Shea JJ, Hennighausen L, Ernst M, Hunter CA. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol. 2006;7:937.PubMedCrossRefGoogle Scholar
  42. 42.
    Batten M, Li J, Yi S, Kljavin NM, Danilenko DM, Lucas S, Lee J, de Sauvage FJ, Ghilardi N. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immunol. 2006;7:929.PubMedCrossRefGoogle Scholar
  43. 43.
    Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 2007;317:256.PubMedCrossRefGoogle Scholar
  44. 44.
    Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M, Kuchroo VK, Hafler DA. IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 2008;454:350.PubMedCrossRefGoogle Scholar
  45. 45.
    Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol. 2008;x9:641.PubMedCrossRefGoogle Scholar
  46. 46.
    Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, Sudo K, Iwakura Y. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol. 2006;177:566.PubMedGoogle Scholar
  47. 47.
    Matusevicius D, Kivisakk P, He B, Kostulas N, Ozenci V, Fredrikson S, Link H. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler. 1999;5:101.PubMedGoogle Scholar
  48. 48.
    Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity 2004;21:467.PubMedCrossRefGoogle Scholar
  49. 49.
    Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, Saito S, Inoue K, Kamatani N, Gillespie MT, Martin TJ, Suda T. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999;103:1345.PubMedCrossRefGoogle Scholar
  50. 50.
    Hirota K, Hashimoto M, Yoshitomi H, Tanaka S, Nomura T, Yamaguchi T, Iwakura Y, Sakaguchi N, Sakaguchi S. T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis. J Exp Med. 2007;204:41.PubMedCrossRefGoogle Scholar
  51. 51.
    Nakae S, Saijo S, Horai R, Sudo K, Mori S, Iwakura Y. IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc Natl Acad Sci USA. 2003;100:5986.PubMedCrossRefGoogle Scholar
  52. 52.
    Nakae S, Nambu A, Sudo K, Iwakura Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol. 2003;171:6173.PubMedGoogle Scholar
  53. 53.
    Lubberts E, Koenders MI, van den Berg WB. The role of T-cell interleukin-17 in conducting destructive arthritis: lessons from animal models. Arthritis Res Ther. 2005;7:29.PubMedCrossRefGoogle Scholar
  54. 54.
    Lubberts E, Koenders MI, Oppers-Walgreen B, van den Bersselaar L, Coenen-de Roo CJ, Joosten LA, van den Berg WB. Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Arthritis Rheum. 2004;50:650.PubMedCrossRefGoogle Scholar
  55. 55.
    van Beelen AJ, Teunissen MB, Kapsenberg ML, de Jong EC. Interleukin-17 in inflammatory skin disorders. Curr Opin Allergy Clin Immunol. 2007;7:374.PubMedCrossRefGoogle Scholar
  56. 56.
    Teunissen MB, Koomen CW, de Waal Malefyt R, Wierenga EA, Bos JD. Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes. J Invest Dermatol. 1998;111:645.PubMedCrossRefGoogle Scholar
  57. 57.
    Ma HL, Liang S, Li J, Napierata L, Brown T, Benoit S, Senices M, Gill D, Dunussi-Joannopoulos K, Collins M, Nickerson-Nutter C, Fouser LA, Young DA. IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation. J Clin Invest. 2008;118:597.PubMedGoogle Scholar
  58. 58.
    Wong CK, Lit LC, Tam LS, Li EK, Wong PT, Lam CW. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin Immunol. 2008;127:385.PubMedCrossRefGoogle Scholar
  59. 59.
    Seiderer J, Elben I, Diegelmann J, Glas J, Stallhofer J, Tillack C, Pfennig S, Jurgens M, Schmechel S, Konrad A, Goke B, Ochsenkuhn T, Muller-Myhsok B, Lohse P, Brand S. Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohn’s disease and analysis of the IL17F p.His161Arg polymorphism in IBD. Inflamm Bowel Dis. 2008;14:437.PubMedCrossRefGoogle Scholar
  60. 60.
    Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Schwarzenberger P, Oliver P, Huang W, Zhang P, Zhang J, Shellito JE, Bagby GJ, Nelson S, Charrier K, Peschon JJ, Kolls JK. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J Exp Med. 2001;194:519.PubMedCrossRefGoogle Scholar
  61. 61.
    Ye P, Garvey PB, Zhang P, Nelson S, Bagby G, Summer WR, Schwarzenberger P, Shellito JE, Kolls JK. Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am J Respir Cell Mol Biol. 2001;25:335.PubMedGoogle Scholar
  62. 62.
    Happel KI, Lockhart EA, Mason CM, Porretta E, Keoshkerian E, Odden AR, Nelson S, Ramsay AJ. Pulmonary interleukin-23 gene delivery increases local T-cell immunity and controls growth of Mycobacterium tuberculosis in the lungs. Infect Immun. 2005;73:5782.PubMedCrossRefGoogle Scholar
  63. 63.
    Romani L, Zelante T, De Luca A, Fallarino F, Puccetti P. IL-17 and therapeutic kynurenines in pathogenic inflammation to fungi. J Immunol. 2008;180:5157.PubMedGoogle Scholar
  64. 64.
    Zelante T, Bozza S, De Luca A, D’Angelo C, Bonifazi P, Moretti S, Giovannini G, Bistoni F, Romani L. Th17 cells in the setting of Aspergillus infection and pathology. Med Mycol. 2008;12:1.CrossRefGoogle Scholar
  65. 65.
    Aujla SJ, Dubin PJ, Kolls JK. Interleukin-17 in pulmonary host defense. Exp Lung Res. 2007;33:507.PubMedCrossRefGoogle Scholar
  66. 66.
    Aujla SJ, Dubin PJ, Kolls JK. Th17 cells and mucosal host defense. Semin Immunol. 2007;19:377.PubMedCrossRefGoogle Scholar
  67. 67.
    Khader SA, Bell GK, Pearl JE, Fountain JJ, Rangel-Moreno J, Cilley GE, Shen F, Eaton SM, Gaffen SL, Swain SL, Locksley RM, Haynes L, Randall TD, Cooper AM. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol. 2007;8:369.PubMedCrossRefGoogle Scholar
  68. 68.
    Fontenot JD, Rudensky AY. Molecular aspects of regulatory T cell development. Semin Immunol. 2004;16:73.PubMedCrossRefGoogle Scholar
  69. 69.
    Ziegler SF. FOXP3: of mice and men. Annu Rev Immunol. 2006;24:209.PubMedCrossRefGoogle Scholar
  70. 70.
    Battaglia M, Gregori S, Bacchetta R, Roncarolo MG. Tr1 cells: from discovery to their clinical application. Semin Immunol. 2006;18:120.PubMedCrossRefGoogle Scholar
  71. 71.
    Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001;27:68.PubMedCrossRefGoogle Scholar
  72. 72.
    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.PubMedCrossRefGoogle Scholar
  73. 73.
    Marie JC, Liggitt D, Rudensky AY. Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity 2006;25:441.PubMedCrossRefGoogle Scholar
  74. 74.
    Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlsson S. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA. 1993;90:770.PubMedCrossRefGoogle Scholar
  75. 75.
    Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol. 2005;6:1142.PubMedCrossRefGoogle Scholar
  76. 76.
    Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, Blank RB, Meylan F, Siegel R, Hennighausen L, Shevach EM, O’Shea J. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 2007;26:371.PubMedCrossRefGoogle Scholar
  77. 77.
    Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY, Ziegler SF, Littman DR. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 2008;453:236.PubMedCrossRefGoogle Scholar
  78. 78.
    Okuda Y, Sakoda S, Bernard CC, Fujimura H, Saeki Y, Kishimoto T, Yanagihara T. IL-6-deficient mice are resistant to the induction of experimental autoimmune encephalomyelitis provoked by myelin oligodendrocyte glycoprotein. Int Immunol. 1998;10:703.PubMedCrossRefGoogle Scholar
  79. 79.
    Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007;8:967.PubMedCrossRefGoogle Scholar
  80. 80.
    Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057.PubMedCrossRefGoogle Scholar
  81. 81.
    Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4:330.PubMedCrossRefGoogle Scholar
  82. 82.
    Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2003;299:1033.PubMedCrossRefGoogle Scholar
  83. 83.
    Korn T, Reddy J, Gao W, Bettelli E, Awasthi A, Petersen TR, Backstrom BT, Sobel RA, Wucherpfennig KW, Strom TB, Oukka M, Kuchroo VK. Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat Med. 2007;13:423.PubMedCrossRefGoogle Scholar
  84. 84.
    Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997;389:737.PubMedCrossRefGoogle Scholar
  85. 85.
    de Waal Malefyt R, Haanen J, Spits H, Roncarolo MG, te Velde A, Figdor C, Johnson K, Kastelein R, Yssel H, de Vries JE. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med. 1991;174:915.PubMedCrossRefGoogle Scholar
  86. 86.
    Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 1993;75:263.PubMedCrossRefGoogle Scholar
  87. 87.
    Rakoff-Nahoum S, Hao L, Medzhitov R. Role of toll-like receptors in spontaneous commensal-dependent colitis. Immunity 2006;25:319.PubMedCrossRefGoogle Scholar
  88. 88.
    Awasthi A, Carrier Y, Peron JP, Bettelli E, Kamanaka M, Flavell RA, Kuchroo VK, Oukka M, Weiner HL. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol. 2007;8:1380.PubMedCrossRefGoogle Scholar
  89. 89.
    Stumhofer JS, Silver JS, Laurence A, Porrett PM, Harris TH, Turka LA, Ernst M, Saris CJ, O’Shea JJ, Hunter CA. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat Immunol. 2007;8:1363.PubMedCrossRefGoogle Scholar
  90. 90.
    Fitzgerald DC, Zhang GX, El-Behi M, Fonseca-Kelly Z, Li H, Yu S, Saris CJ, Gran B, Ciric B, Rostami A. Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nat Immunol. 2007;8:1372.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Amit Awasthi
    • 1
  • Gopal Murugaiyan
    • 1
  • Vijay K. Kuchroo
    • 1
  1. 1.Center for Neurologic Diseases, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA

Personalised recommendations