T-bet: A Critical Regulator of Encephalitogenic T Cells



T-bet is a transcription factor that regulates CD4 Th1 cell differentiation and mice deficient in T-bet fail to develop experimental autoimmune encephalomyelitis, demonstrating its critical role in the generation of immune-mediated demyelinating disease. More importantly, silencing T-bet in a model for multiple sclerosis (MS) demonstrates that it is a viable therapeutic target. T-bet has been found to correlate with disease activity and therapeutic efficacy, suggesting that it may also be a biomarker for MS. Defining the role of T-bet in generating encephalitogenic T cells and their effector functions may provide insight into the mechanisms that underlie the pathology of MS lesions.


Multiple Sclerosis Experimental Autoimmune Encephalomyelitis Multiple Sclerosis Patient Multiple Sclerosis Lesion Experimental Autoimmune Encephalomyelitis Induction 
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  1. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Salluston F (2007) Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 8:942–949PubMedCrossRefGoogle Scholar
  2. Afkarian M, Sedy JR, Yang J, Jacobson NG, Cereg N, Yang SY, Murphy TL, Murphy KM (2002) T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells. Nat Immunol 3:549–557PubMedCrossRefGoogle Scholar
  3. Anderson AC, Lord GM, Dardalhon V, Lee DH, Sabatos-Peyton CA, Glimcher LH, Kuchroo VK (2010) T-bet, a Th1 transcription factor regulates the expression of Tim-3. Eur J Immunol 40:859–866PubMedCrossRefGoogle Scholar
  4. Ando DG, Clayton J, Dono D, Urban JL, Sercarz EE (1989) Encephalitogenic T cells in the B10.PL model of experimental allergic encephalomyelitis (EAE) are of the Th-1 lymphokine subtype. Cell Immunol 124:132–43PubMedCrossRefGoogle Scholar
  5. Annunziata P, Morana P, Giorgio A, Galeazzi M, Campanella V, Lore F et al (2003) High frequency of psoriasis in relatives is associated with early onset in an Italian multiple sclerosis cohort. Acta Neurol Scand 108:327–331PubMedCrossRefGoogle Scholar
  6. Baerwald KD, Popko B (1998) Developing and mature oliodendrocytes respond differently to the immune cytokine interferon-gamma. J Neurosci Res 52:230–239PubMedCrossRefGoogle Scholar
  7. Becher B, Durell BG, Noelle R (2002) Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J Clin Invest 110:493–497PubMedGoogle Scholar
  8. Becher B, Durell BG, Noelle RJ (2003) IL-23 produced by CNS-resident cells controls T cell encephalitogenicity during the effector phase of experimental autoimmune encephalomyelitis. J Clin Invest 112:1186–1191PubMedGoogle Scholar
  9. Beima KM, Miazgowicz MM, Lewis MD, Yan PS, Huang TH, Weinmann AS (2006) T-bet binding to newly identified target gene promoters is cell type-independent but results in variable context-dependent functional effects. J Biol Chem 281:11992–12000Google Scholar
  10. Bergamaschi R, Villani S, Crabbio M, Ponzio M, Romani A, Verri A et al (2009) Inverse relationship between multiple sclerosis and allergic respiratory diseases. Neurol Sci 30:115–118PubMedCrossRefGoogle Scholar
  11. Bettelli E, Sullivan B, Szabo SJ, Sobel RA, Glimcher LH, Kuchroo VK (2004) Loss of T-bet but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J Exp Med 200:79–87PubMedCrossRefGoogle Scholar
  12. Bettelli E, Carrier Y, Gao W, Kom T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238PubMedCrossRefGoogle Scholar
  13. Bornsen L, Khademi M, Olsson T, Sorensen PS, Sellebjerg F (2011) Osteopontin concentrations are increased in cerebrospinal fluid during attacks of multiple sclerosis. Mult Scler 17:32–42PubMedCrossRefGoogle Scholar
  14. Chabas D, Baranzini SE, Mitchell D, Bernard CC, Rittling SR, Denhardt DT, Sobel RA, Lock C, Karpuj M, Pedotti R, Heller R, Oksenberg JR, Steinman L (2001) The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294:1731–1735PubMedCrossRefGoogle Scholar
  15. Charcot JM (1968) Histologie de la sclerose en plaques Gazette des hopitaux. Paris 41:554–555Google Scholar
  16. Chen Y, Langrish CL, McKenzie B, Joyce-Shaikh B, Stumhofer JS, McClanahan T, Blumenschein W, Churakovsa T, Low J, Presta L, Hunter CA, Kastelein RA, Cua DJ (2006) Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J Clin Invest 116:1317–26PubMedCrossRefGoogle Scholar
  17. Chitnis T, Najafian N, Benou C, Salama AD, Grusby MJ, Sayegh MH, Khoury SJ (2001) Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis. J Clin Invest 108:739–747PubMedGoogle Scholar
  18. Codarri L, Gyulveszi G, Tosevski V, Hesske L, Fontana A, Magnenat L, Suter T, Becher B (2011) RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 12:560–567PubMedCrossRefGoogle Scholar
  19. 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 (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421:744–748PubMedCrossRefGoogle Scholar
  20. Drulovic J, Savic E, Pekmezovic T, Mesaros S, Stojavljevic N, Dujmovic-Basiroski I, Kostic J, Vasic V, Stojkovic MM, Popadic D (2009) Expression of Th1 and Th17 cytokines and transcription factors in multiple sclerosis patients: Does baseline T-bet mRNA predict the response to interferon-beta treatment? J Neuroimmunol 215:90–95PubMedCrossRefGoogle Scholar
  21. Dubey C, Croft M, Swain SL (1996) Naïve and effector CD4 T cells differ in their requirements for T cell receptor versus costimulatory signals. J Immunol 157:3280–3289PubMedGoogle Scholar
  22. El-Behi M, Ciric B, Dai H, Yan Y, Cullimore M, Safavi F, Zhang GX, Dittel BN, Rostami A (2011) The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol 12:568–575PubMedCrossRefGoogle Scholar
  23. Ferber IA, Brock S, Taylor-Edwards C, Ridgway W, Dinisco C, Steinman L, Dalton D, Fathman CG (1996) Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol 156:5–7PubMedGoogle Scholar
  24. Finotto S, Neurath MF, Glickman JN, Qin S, Lehr HA, Green FH, Ackerman K, Haley K, Galle PR, Szabo SJ, Drazen JM, De Sanctis GT, Glimcher LH (2002) Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science 295:336–338PubMedCrossRefGoogle Scholar
  25. Frisullo G, Angelucci F, Caggiula M, Nociti V, Iorio R, Patanella AK, Sancricca C, Mirabella M, Tonali PA, Batocchi AP (2006) pSTAT1, pSTAT3, and T-bet expression in peripheral blood mononuclear cells from relapsing-remitting multiple sclerosis patients correlates with disease activity. J Neurosci Res 84:1027–1036PubMedCrossRefGoogle Scholar
  26. Frisullo G, Nociti V, Iorio R, Patanella KA, Bianco A, Caggiula M, Sancricca C, Tonali PA, Mirabella M, Batocchi AP (2007) Glucocorticoid treatment reduces T-bet and pSTAT1 expression in mononuclear cells from relapsing remitting multiple sclerosis patients. Clin Immunol 124:284–293PubMedCrossRefGoogle Scholar
  27. Frisullo G, Nociti V, Iorio R, Patanella AK, Caggiula M, Marti A, Sancricca C, Angelucci F, Mirabella M, Tonali PA, Batocchi AP (2009) Regulatory T cells fail to suppress CD4+ T-bet + T cells in relapsing multiple sclerosis patients. Immunology 127:418–428PubMedCrossRefGoogle Scholar
  28. Frisullo G, Iorio R, Plantone D, Marti A, Nociti V, Patanella AD, Batocchi AP (2011) CD4+ T-bet+, CD4+ pSTAT3+ and CD8+ T-bet+ T cells accumulate in peripheral blood during NZB treatment. Mult Scler 17:556–566PubMedCrossRefGoogle Scholar
  29. Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, Grainger JR, Chen Q, Kanno Y, Watford WT, Sun HW, Eberl G, Shevach EM, Belkaid Y, Cua DJ, Chen W, O’Shea JJ (2010) Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling. Nature 467(7318):967–971. doi: 10.1038/nature09447PubMedCrossRefGoogle Scholar
  30. Gielen AW, Lobell A, Lidman O, Khademi M, Olsson T, Piehl F (2005) Expression of T cell immunoglobulin- and mucin-domain-containing molecules-1 and -3 (TIM-1 and -3) in the rat nervous and immune systems. J Neuroimmunol 164:93–104PubMedCrossRefGoogle Scholar
  31. Gocke AR, Cravens PD, Ben LH, Hussain RZ, Northrop SC, Racke MK, Lovett-Racke AE (2007) T-bet regulates the fate of Th1 and Th17 lymphocytes in autoimmunity. J Immunol 178:1341–1348PubMedGoogle Scholar
  32. Gorelik L, Constant S, Flavell RA (2002) Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J Exp Med 195:1499–1505PubMedCrossRefGoogle Scholar
  33. Gran B, Zhang GX, Yu S, Li J, Chen XH, Ventura ES, Kamoun M, Rostami A (2002) 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 169:7104–7410PubMedGoogle Scholar
  34. Guerau-de-Arellano M, Smith KM, Godlewski J, Liu Y, winger R, Lawler SE, Whitacre CC, Racke MK, Lovett-Racke AE (2011) Micro-RNA dysregulation in multiple sclerosis favours pro-inflammatory T-cell-mediated autoimmunity. Brain 134:3578–89PubMedCrossRefGoogle Scholar
  35. Haak S, Croxford AL, Dreymborg K, Heppner FL, Pouly S, Becher B, Waisman A (2009) IL-17 A and IL-17 F do not contribute vitally to autoimmune neuro-inflammation in mice. J Clin Invest 119:61–69PubMedGoogle Scholar
  36. Heremans H, Dillen C, Groenen M, Martens E, Billiau A (1996) Chronic relapsing experimental autoimmune encephalomyelitis (CREAE) in mice: enhancement by monoclonal antibodies against interferon-gamma. Eur J Immunol 26:2393–2398PubMedCrossRefGoogle Scholar
  37. Hori S, Takahashi T, Sakaguchi S (2003) Control autoimmunity by naturally arising regulatory CD4+ T cells. Adv Immunol 81:331–371PubMedCrossRefGoogle Scholar
  38. Hou J, Schindler U, Henzel WJ, Ho TC, Brasseur M, McKnight SL (1994) An interleukin-4-induced transcription factor: IL-4 Stat. Science 265:1701–1706PubMedCrossRefGoogle Scholar
  39. Hsieh CS, Heimberger AB, Gold JS, O’Garra A, Murphy KM (1992) Differential regulation of T helper phenotype development by interleukin 4 and 10 in an alpha beta T-cell-receptor transgenic system. Proc Natl Acad Sci U S A 89:6065–6069PubMedCrossRefGoogle Scholar
  40. Hur EM, Youssef S, Haws ME, Zhang SY, Sobel RA, Steinman L (2007) Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells. Nat Immunol 8:74–83PubMedCrossRefGoogle Scholar
  41. Hwang ES, Szabo SJ, Schwartzberg PL, Glimcher LH (2005) T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 307:430–343PubMedCrossRefGoogle Scholar
  42. Iorio R, Frisullo G, Nociti V, Patanella KA, Bianco A, Marti A, Mirabella M, Tonali PA, Batocchi AP (2009) T-bet pSTAT1 and pSTAT3 expression in peripheral blood mononuclear cells during pregnancy correlates with post-partum activation of multiple sclerosis. Clin Immunol 131:70–83PubMedCrossRefGoogle Scholar
  43. Jacobson NF, Szabo SJ, Weber-Nordt RM, Zhong Z, Schreiber RD, Darnell JE, Murphy KM (1995) Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat) 3 and Stat4. J Exp Med 181:1755–1762PubMedCrossRefGoogle Scholar
  44. Jansson M, Panoutsakopoulou V, Baker J, Klein L, Cantor H (2002) Cutting edge: Attenuated experimental autoimmune encephalomyelitis in eta-1/osteopontin-deficient mice. J Immunol 168:2096–2099PubMedGoogle Scholar
  45. Jenner RG, Townsend MJ, Jackson I, Sun K, Bouwman RD, Young RA, Glimcher LH, Lord GM (2009) The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes. Proc Natl Acad Sci U S A 106:17876–17881PubMedCrossRefGoogle Scholar
  46. June CH, Ledbetter JA, Linsley PS, Thompson CB (1990) Role of the CD28 receptor in T-cell activation. Immunol Today 11:211–216PubMedCrossRefGoogle Scholar
  47. Karni A, Abramsky O (1999) Association of MS with thyroid disorders. Neurology 53:883–885PubMedCrossRefGoogle Scholar
  48. Khademi M, Illes Z, Gielen AW, Marta M, Takazawa N, Baecher-Allan C, Brundin L, Hannerz J, Martin C, Harris RA, Hafler DA, Kuchroo VK, Olsson T, Piehl F, Wallstrom E (2004) T cell Ig- and mucin-domain-containing molecule-3 (TIM-3) and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis. J Immunol 172:7169–7176PubMedGoogle Scholar
  49. Kleiter I, Song J, Lukas D, hasan M, Neumann B, Croxford AL, Pedre X, Hovelmeyer N, Yogev N, Mildner A, Prinz M, Wiese e, Reifenberg K, Bittner S, Siendl H, Steinman L, Becker C, Bogdahn U, Neurath MF, Steinbrecher A, Waisman A (2010) Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis. Brain 133:1067–1081PubMedCrossRefGoogle Scholar
  50. Koguchi K, Anderson DE, Yang L, O’Connor KC, Kuchroo VK, Hafler DA (2006) Dysregulated T cell expression of TIM3 in multiple sclerosis. J Exp Med 203:1413–1418PubMedCrossRefGoogle Scholar
  51. Kohler RE, Comerford I, Townley S, Haylock-Jacobs S, Clark-Lewis I, McColl SR (2008) Antagonism of the chemokine receptors CXCR3 and CXCR4 reduces the pathology of experimental autoimmune encephalomyelitis. Brain Pathol 18:504–516PubMedGoogle Scholar
  52. Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, Suko K, Iwakura Y (2006) IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 177:566–573PubMedGoogle Scholar
  53. Korn-Lubetzki I, Kahana E, Cooper G, Abramsky O (1984) Activity of multiple sclerosis during pregnancy and puerperium. Ann Neurol 16:229–231PubMedCrossRefGoogle Scholar
  54. Kroenke MA, Segal BM (2007) Th17 and Th1 responses directed against the immunizing epitope, as opposed to secondary epitopes, dominate the autoimmune repertoire during relapses of experimental autoimmune encephalomyelitis. J Neurosci Res 85:1685–1693Google Scholar
  55. Kumar V, Stellrecht K, Sercarz E (1996) Inactivation of T cell receptor peptide-specific CD4 regulatory T cells induces chronic experimental autoimmune encephalomyelitis (EAE). J Exp Med 184:1609–1617Google Scholar
  56. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–40PubMedCrossRefGoogle Scholar
  57. Lees JR, Iwakura Y, Russell JH (2008) Host T cells are the main producers of IL-17 within the central nervous system during initiation of experimental autoimmune encephalomyelitis induced by adoptive transfer of Th1 cell lines. J Immunol 180:8066–72PubMedGoogle Scholar
  58. Lewis MD, Miller SA, Miazgowicz MM, Beima KM, Weinmann AS (2007) T-bet’s ability to regulate individual target genes requires the conserved T-box domain to recruit histone methyltransferase activity and a separate family member-specific transactivation domain. Mol Cell Biol 27:8510–8521PubMedCrossRefGoogle Scholar
  59. Liu L, Huang D, Matsui M, He TT, Hu T, Demartino J, Lu B, Gerard C, Ransohoff RM (2006) Severe disease, unaltered leukocyte migration, and reduced IFN-gamma production in CXCR3-/- mice with experimental autoimmune encephalomyelitis. J Immunol 176:4399–4409PubMedGoogle Scholar
  60. Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, Langer-Gould A, Strober S, Cannella B, Allard J, Klonowski P, Austin A, Lad N, Kaminski N, Galli SJ, Oksenberg JK, Raine CS, Heller R, Steinman L (2002) Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 8:500–508PubMedCrossRefGoogle Scholar
  61. Lord GM, Rao RM, Choe H, Sullivan BM, Lichtman AH, Luscinskas FW, Glimcher LH (2005) T-bet is required for optimal proinflammatory CD4+ T-cell trafficking. Blood 106:3432–3439PubMedCrossRefGoogle Scholar
  62. Lovett-Racke AE, Trotter JL, Lauber J, Perrin PJ, June CH, Racke MK (1998) Decreased dependence of myelin basic protein-reactive T cells on CD28-mediated costimulation in multiple sclerosis patients. A marker of activated/memory T cells. J Clin Invest 101:725–730PubMedCrossRefGoogle Scholar
  63. Lovett-Racke AE, Rocchini AE, Choy J, Northrop SC, Hussain RZ, Ratts RB, Sikder D, Racke MK (2004) Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes. Immunity 21:719–731PubMedCrossRefGoogle Scholar
  64. Lublin FD, Knobler RL, Kalman B, Goldhaber M, Marini J, Perrault M, D’Imperio C, Joseph J, Alkan SS, Korngold R (1993) Monoclonal anti-gamma interferon antibodies enhance experimental allergic encephalomyelitis. Autoimmunity 16:267–274PubMedCrossRefGoogle Scholar
  65. Ma F, Xu S, Liu X, Zhang Q, Xu X, Liu M, Hua M, Li N, Yao H, Cao X (2011) The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-γ. Nat Immunol 12:861–869PubMedCrossRefGoogle Scholar
  66. Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT (2006) Transforming growth factor-β induces development of the Th17 lineage. Nature 441:231–234PubMedCrossRefGoogle Scholar
  67. Marie JC, Letterio JJ, Gavin M, Rudensky AY (2005) TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+ CD25 + regulatory T cells. J Exp Med 201:1061–1067PubMedCrossRefGoogle Scholar
  68. McDonald AH, Swanborg RH (1988) Antigen-specific inhibition of immune interferon production by suppressor cells of autoimmune encephalomyelitis. J Immunol 140:1132–1138PubMedGoogle Scholar
  69. Miller SA, Huang AC, Miazgowicz MM, Brassil MM, Weinmann AS (2008) Coordinated but physically separable interaction with H3K27-demethylase and H3K4-methyltransferase activities are required for T-box protein-mediated activation of developmental gene expression. Genes Dev 22:2980–2993PubMedCrossRefGoogle Scholar
  70. Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA, Freeman GJ, Kuchroo VK (2002) Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415:536–541PubMedCrossRefGoogle Scholar
  71. Mosmann TR, Cherwinski H, Bond MS, Giedlin MA, Coffman RL (1986) Two types of murine helper T cell clones. I Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136:2348–2357PubMedGoogle Scholar
  72. Muller M, Carter SL, Hofer MJ, Manders P, Getts DR, Getts MT, Dreykluft A, Lu B, Gerard C, King NJ, Campbell IL (2007) CXCR3 signaling reduces severity of experimental autoimmune encephalomyelitis by controlling the parenchymal distribution of effector and regulatory T cells in the central nervous system. J Immunol 179:2774–2786PubMedGoogle Scholar
  73. Nath N, Giri S, Prasad R, Singh AK, Singh I (2004) Potential targets of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for multiple sclerosis therapy. J Immunol 172:1273–1286PubMedGoogle Scholar
  74. Nath N, Prasad R, Giri S, Singh AK, Singh I (2006) T-bet is essential for the progression of experimental autoimmune encephalomyelitis. Immunology 118:384–391PubMedCrossRefGoogle Scholar
  75. Ni J, Zhu YN, Zhong XG, Ding Y, Hou LF, Tong XK, Tang W, Ono S, Yang YF, Zuo JP (2009) The chemokine receptor antagonist, TAK-779, decreased experimental autoimmune encephalomyelitis by reducing inflammatory cell migration into the central nervous system, without affecting T cell function. Br J Pharmacol 158:2046–2056PubMedCrossRefGoogle Scholar
  76. Nielsen NM, Westergaard T, Frisch M, Rostgaard K, Wohlfahrt J, Koch-Henriksen N et al (2006) Type 1 diabetes and multiple sclerosis: A Danish population-based cohort study. Arch Neurol 63:1001–1004PubMedCrossRefGoogle Scholar
  77. Oestreich KJ, Huang AC, Weinmann AS (2011) The lineage-defining factors T-bet and Bcl-6 collaborate to regulate Th1 gene expression patterns. J Exp Med 208:1001–1013PubMedCrossRefGoogle Scholar
  78. 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, Waal-Malefyt R de, Hannum C, Bazan JF, Kastelein RA (2000) Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13:715–725PubMedCrossRefGoogle Scholar
  79. Panitch HS, Hirsch RL, Haley AS, Johnson KP (1987) Exacerbation of multiple sclerosis in patients treated with gamma interferon. Lancet 1:893–895PubMedCrossRefGoogle Scholar
  80. Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, Pflanz S, Zhang R, Singh KP, Vega F, To W, Wagner J, O’Farrell AM, McClanahan T, Zurawski S, Hannum C, Gorman D, Rennick DM, Kastelein RA, de Waal Malefyt R, Moore KW (2002) A receptor for the heterodimeric cytokine IL-23 is composed of IL- 12Rbeta1 and a novel cytokine receptor subunit IL-23R. J Immunol 168:5699–5708PubMedGoogle Scholar
  81. Park IK, Shultz LD, Letterio JJ, Gorham JD (2005) TGF-beta1 inhibits T-bet induction by IFN-gamma in murine CD4+ T cells through the protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1. J Immunol 175:5666–5674PubMedGoogle Scholar
  82. Paulos CM, Carpenito C, Plesa G, Suhoski MM, Varela-Rohena A, Golovina TN, Carroll RG, Riley JL, June CH (2010) The inducible costimulator (ICOS) is critical for the development of human T(H)17 cells. Sci Transl Med 2:55ra78PubMedCrossRefGoogle Scholar
  83. Pedotti R, Farinotti M, Falcone C, Borgonovo L, Confalonieri P, Campanella A et al (2009) Allergy and multiple sclerosis: a population-based case-control study. Mult Scler 15:899–906PubMedCrossRefGoogle Scholar
  84. Peng X, Jin J, Montes M, Sujkowski D, Tang Y, Smrtka J, Vollmer T, Singh I, Markovic-Plese S (2006) Immunomodulatory effects of 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors, potential therapy for relapsing remitting multiple sclerosis. J Neuroimmunol 178:130–139PubMedCrossRefGoogle Scholar
  85. Ponomarev ED, Shriver LP, Maresz K, Pedras-Vasconcelos J, Verthelyi D, Dittel BN (2007) GM-CSF production by autoreactive T cells is required for the activation of microglial cells and the onset of experimental autoimmune encephalomyelitis. J Immunol 178:39–48PubMedGoogle Scholar
  86. Qin S, Rottman JB, Myers P, Kasam N, Weinblatt M, Loetscher M, Koch AE, Moser B, Mackay CR (1998) The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest 101:746–754PubMedCrossRefGoogle Scholar
  87. Racke MK, Bonomo A, Scott DE, Cannella B, Levine A, Raine CS, Shevach EM, Rocken M (1994) Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. J Exp Med 180:1961–1966PubMedCrossRefGoogle Scholar
  88. Racke MK, Burnett D, Pak SH, Albert PS, Cannella B, Raine CS, McFarlin DE, Scott DE (1995) Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course. J Immunol 154:450–458PubMedGoogle Scholar
  89. Rivers RM, Spunt DH, Berry GP (1933) Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J Exp Med 58:39–53PubMedCrossRefGoogle Scholar
  90. Roquer J, Escudero D, Herraiz J, Maso E, Cano F (1987) Multiple sclerosis and Hashimoto’s thyroiditis. J Neurol 234:23–24PubMedCrossRefGoogle Scholar
  91. Rottman JB, Smith T, Tonra JR, Ganley K, Bloom T, Silva R, Pierce B, Gutierrez-Ramos JC, Ozkaynak E, Coyle AJ (2001) The costimulatory molecule ICOS plays an important role in the immunopathogenesis of EAE. Nat Immunol 2:605–611PubMedCrossRefGoogle Scholar
  92. Sallusto F, Lenig D, Mackay CR, Lanzavecchia A (1998) Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med 187:875–883PubMedCrossRefGoogle Scholar
  93. Shinohara ML, Jansson M, Hwang ES, Werneck MK, Glimcher LH, Cantor H (2005) T-bet-dependent expression of osteopontin contributes to T cell polarization. Proc Natl Acad Sci U S A 102:17101–17106PubMedCrossRefGoogle Scholar
  94. Skurkovich S, Boilo A, Beliaeva I, Buglak A, Alekseeva T, Smirnova N, Kulakova O, Tchechonin V, Gurova O, Deomina T, Favorova OO, Skurkovic B, Gusev E (2001) Randomized study of antibodies to IFN-gamma and TNF-alpha in secondary progressive multiple sclerosis. Mult Scler 7:277–284PubMedGoogle Scholar
  95. Sloka S (2002) Observations on recent studies showing increased co-occurrence of autoimmune diseases. J Autoimmun 18:251–257PubMedCrossRefGoogle Scholar
  96. Smith KM, Guerau-de-Arellano M, Costinean S, Williams JL, Bottoni A, Mavrikis Cox G, Satoskar AR, Croce CM, Racke MK, Lovett-Racke AE, Whitacre CC (2012) miR-29ab1 deficiency identifies a negative feedback loop controlling Th1 bias that is dysregulated inmultiple sclerosis. J Immunol 189(4):1567–1576. doi: 10.4049/jimmunol.1103171. (Epub 2012 Jul 6)PubMedCrossRefGoogle Scholar
  97. Sporici RA, Beswick RL, von Allmen C, Rumbley CA, Hayden-Ledbetter M, Ledbetter JA, Perrin PJ (2001) ICOS ligand costimulation is required for T-cell encephalitogenicity. Clin Immunol 100:277–288PubMedCrossRefGoogle Scholar
  98. Sporici R, Issekutz TB (2010) CXCR3 blockade inhibits T-cell migration into the CNS during EAE and prevents development of adoptively transferred, but not actively induced disease. Eur J Immunol 40:2751–2761PubMedCrossRefGoogle Scholar
  99. Steiner DF, Thomas MF, Hu JK, Yang Z, Babiarz JE, Allen CD, Matloubian M, Blelloch R, Ansel KM (2011) MicroRNA-29 regulates T-box transcription factors and interferon-γ production in helper T cells. Immunity 36:169–181Google Scholar
  100. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH (2000) A novel transcription factor, T-bet directs th1 lineage commitment. Cell 100:655–669PubMedCrossRefGoogle Scholar
  101. Szabo SJ, Sullivan BM, Stemmann C, Satoskar AR, Sleckman BP, Glimcher LH (2002) Distinct effects of T-bet in Th1 lineage commitment and IFN-γ production in CD4 and CD8 T cells. Science 295:338–342PubMedCrossRefGoogle Scholar
  102. Tan AH, Goh SY, Wong SC, Lam KP (2008) T helper cell-specific regulation of inducible costimulator expression via distinct mechanisms mediated by T-bet and GATA-3. J Biol Chem 283:128–136PubMedCrossRefGoogle Scholar
  103. Traugott U, Lebon P (1988) Multiple sclerosis: involvement of interferons in lesion pathogenesis. Ann Neurol 24:243–251PubMedCrossRefGoogle Scholar
  104. Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, Fugger L (2008) Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 172:146–155Google Scholar
  105. Vartanian T, Li Y, Zhao M, Stefansson K (1995) Interferon-gamma-induced oligodendrocyte cell death: implications for the pathogenesis of multiple sclerosis. Mol Med 1:732–743PubMedGoogle Scholar
  106. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFbeta in the context of an inflammatory cytokine nilieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189PubMedCrossRefGoogle Scholar
  107. Waldburger KE, Hastings RC, Schaub RG, Goldman SL, Leonard JP (1996) Adoptive transfer of experimental allergic encephalomyelitis after in vitro treatment with recombinant murine interleukin-12. Preferential expansion of interferon-gamma-producing cells and increased expression of macrophage-associated inducible nitric oxide synthase as immunomodulatory mechanisms. Am J Pathol 148:375–382PubMedGoogle Scholar
  108. Wen ST, Liu GJ, Feng RN, Gong FC, Zhong H, Duan SR, Bi S (2012) Increased levels of IL-23 and osteopontin in serum and cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 244:94–96PubMedCrossRefGoogle Scholar
  109. Willenborg DO, Fordham S, Bernard CC, Cowden WB, Ramshaw IA (1996) IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J Immunol 157:3223–3227PubMedGoogle Scholar
  110. Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, Basham B, Smith K, Chen T, Morel F, Lecron JC, Kastelein RA, Cua DJ, McClanahan TK, Bowman EP, de Waal Malefyt R (2007) Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 8:950–957PubMedCrossRefGoogle Scholar
  111. Yang L, Anderson D, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M, Kuchroo VK and H (2008a) Il-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 454:350–352CrossRefGoogle Scholar
  112. Yang L, Anderson DE, Kuchroo VK, Hafler DA (2008b) Lack of TIM-3 immunoregulation in multiple sclerosis. J Immunol 180:4409–4414Google Scholar
  113. Yang Y, Weiner J, Liu Y, Smith AJ, Huss DJ, Winger R, Peng H, Cravens PD, Racke MK, Lovett-Racke AE (2009) T-bet is essential for encephalitogenicity of both Th1 and Th17 cells. J Exp Med 206:1549–1564PubMedCrossRefGoogle Scholar
  114. Yao Z, Painter SL, Fanslow WC, Ulrich D, Macduff BM, Springs MK, Armitage RJ (1995) Human IL-17: a novel cytokine derived from T cells. J Immunol 155:5483–5486PubMedGoogle Scholar
  115. Yi-qun Z, Joost van Neerven RJ, Kasran A, Boer M de, Ceuppens JL (1996) Differential requirements for co-stimulatory signals from B7 family members by resting versus recently activated memory T cells towards soluble recall antigens. Int Immunol 8:37–44PubMedCrossRefGoogle Scholar
  116. Yura M, Takahashi I, Serada M, Koshio T, Nakagami K, Yuki Y, Kiyono H (2001) Role of MOG-stimulated Th1 type “light up” (GFP+) CD4+ T cells for the development of experimental autoimmune encephalomyelitis (EAE). J Autoimmun 17:17–25PubMedCrossRefGoogle Scholar
  117. Zhang GX, Yu S, Gran B, Li J, Siglienti I, Chen X, Calida D, Ventura E, Kamoun M, Rostami A (2003) Role of IL-12 receptor beta 1 in regulation of T cell response by APC in experimental autoimmune encephalomyelitis. J Immunol 171:4485–4492PubMedGoogle Scholar
  118. Zheng W, Flavell RA (1997) The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89:587–596PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Microbial Infection and ImmunityThe Ohio State UniversityColumbusUSA
  2. 2.Department of NeurologyThe Ohio State UniversityColumbusUSA

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