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The critical role of IL-12 and the IL-12Rβ2 subunit in the generation of pathogenic autoreactive Th1 cells

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Abstract

Experimental Allergic Encephalomyelitis (EAE) is a demyelinating disease of the central nervous system which is an animal model for the human autoimmune disease, multiple sclerosis. EAE is mediated by CD4+ T cells and the T cells responsible for disease induction produce Th1 cytokines. IL-12 produced by monocytes and dendritic cells is the most critical factor which influences the development and differentiation of pathogenic autoreactive Th1 cells. Here, we review our recent studies on the critical contributions of IL-12 and the IL-12Rβ2 subunit to the generation of autoreactive effector cells which mediate EAE. In addition, we discuss the potential contribution of IL-18 to the upregulation of the IL-12/IL-12Rβ2 pathway and the contribution of the suppressor cytokines, IL-4 and IL-10, in downregulating this pathway. Collectively, our studies demonstrate that the IL-12/IL-12Rβ2 pathway is a critical intermediary in the process of Th1 differentiation which can be both positively or negatively regulated. This pathway remains an attractive immunotherapeutic target for blockade of function with inhibitory reagents or downregulation by Th2 cytokines.

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References

  1. Brocke S, Gijbels K, Allegretta M, Ferber I, Piercy C, Blankenstein T, Martin R, Utz U, Karin N, Mitchell D, Veromaa T, Waisman A, Gaur A, Conlon P, Ling N, Fairchild PJ, Wraith DC, O'Garra A, Fathman CG, Steinman L (1996) Treatment of experimental encephalomyelitis with a peptide analogue of myelin basic protein. Nature 379:343

    Google Scholar 

  2. Budinger L, Borradori L,Yee C, Eming R, Ferencik S, Grosse-Wilde H, Merk HF, Yancey K, Hertl M (1998) Identification and characterization of autoreactive T cell responses to bullous pemphigoid antigen in 2 patients and healthy controls. J Clin Inves 102:2082

    Google Scholar 

  3. Chang JT, Shevach EM, Segal BM (1999) Regulation of interleukin (IL)-12 receptor b2 subunit expression by endogenous IL-12: a critical step in the differentiation of pathogenic autoreactive T cells. J Exp Med 189:969

    Google Scholar 

  4. Constantinescu CS, Wysocka M, Hilliard B, Ventura ES, Lavi E, Trinchieri G, Rostami A (1998) Antibodies against IL-12 prevent superantigen-induced and spontaneous relapses of experimental autoimmune encephalomyelitis. J Immunol 161:5097

    Google Scholar 

  5. Cooper AM, Magram J, Ferrante J, Orme IM (1997) Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice infected withMycobacterium tuberculosis. J Exp Med 186:39

    Google Scholar 

  6. D'Andrea A, Aste-Amezaga M, Valiante NM, Ma X, Kubin M, Trinchieri G (1993) Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma- production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med 178:1041

    Google Scholar 

  7. Ding L, Shevach EM (1998) Differential effects of CD28 engagement and IL-12 on T cell activation by altered peptide ligands. J Immunol 161:6614

    Google Scholar 

  8. Ferber IA, Brocke 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

    Google Scholar 

  9. Frei K, Eugster HP, Bopst M, Constantinescu CS, Lavi E, Fontana A (1997) Tumor necrosis factor alpha and lymphotoxin alpha are not required for induction of acute experimental autoimmune encephalomyelitis. J Exp Med 185: 2177

    Google Scholar 

  10. Gately MK, Renzetti LM, Magram J, Stern AS, Adorini L, Gubler U, Presky DH (1998) The interleukin12/interleukin-12-receptor system: role in normal and pathologic immune responses. Annu Rev Immunol 16:495

    Google Scholar 

  11. Germann T, Szeliga J, Hess H, Storkel S, Podlaski FJ, Gately MK, Schmitt E, Rude E (1995) Administration of interleukin 12 in combination with type II collagen induces severe arthritis in DBA/1 mice. Proc Natl Acad Sci USA 94: 4823

    Google Scholar 

  12. Khoruts A, Miller SD, Jenkins MK (1995) Neuroantigen-specific Th2 cells are inefficient suppressors of experimental autoimmune encephalomyelitis induced by effector Th1 cells. J Immunol 155: 5011

    Google Scholar 

  13. Kohno K, Kataoka J, Ohtsuki T, Suemoto Y, Okamoto Y, Usui M, Ikeda M, Kurimoto M (1997) IFN-gamma-inducing factor (IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12. J Immunol 158: 1541

    Google Scholar 

  14. Krakowski M, Owens T (1996) Interferon-gamma confers resistance to experimental allergic encephalomyelitis. Eur J Immunol 26: 1641

    Google Scholar 

  15. Lafaille JJ, Ngashima K, Katsuki M, Tonegawa S (1994) High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice. Cell 78:399

    Google Scholar 

  16. Leonard JP, Waldburger KE, Goldman SJ (1995) Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J Exp Med 181: 381

    Google Scholar 

  17. Liblau RS, Singer SM, McDevitt HO (1995) Th1 and Th2 CD4+ T cells in the pathogenesis of organspecific autoimmune diseases. Immunol Today 16: 34–38

    Google Scholar 

  18. Magram J, Connaughton SE, Warrier RR, Carvajal DM, Wu CY, Ferrante J, Stewart C, Sarmiento U, Faherty DA, Gately MK (1996) IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses. Immunity 4: 471

    Google Scholar 

  19. Martin R, Voskuhl R, Flerlage M, McFarlin DE, McFarland HF (1993) Myelin basic protein-specific T-cell responses in identical twins discordant or concordant for multiple sclerosis. Ann Neurol 34: 524

    Google Scholar 

  20. Mathisen PM, Yu M, Johnson JA, Drazba JA, Tuohy VK (1997) Treatment of experimental autoimmune encephalomyelitis with genetically modified memory T cells. J Exp Med 186: 159

    Google Scholar 

  21. Matthys P, Vermeire K, Mitera T, Heremans H, Huang S, Billiau A (1998) Anti-IL-12 antibody prevents the development and progression of collagen-induced arthritis in IFN-gamma receptor-deficient mice. Eur J Immunol 28:2143

    Google Scholar 

  22. McIntyre KW, Shuster DJ, Gillooly KM, Warrier RR, Connaughton SE, Hall LB, Arp LH, Gately MK, Magram J (1996) Reduced incidence and severity of collagen-induced arthritis in interleukin-12-deficient mice. Eur J Immunol 26: 2933

    Google Scholar 

  23. Micallef MJ, Ohtsuki T, Kohno K, Tanabe F, Ushio S, Namba M, Tanimoto T, Torigoe K, Fujii M, Ikeda M, Fukuda S, Kurimoto M (1996) Interferon-gamma-inducing factor enhances T helper I cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon-gamma production. Eur J Immunol 26: 1647

    Google Scholar 

  24. Moore KW, O'Garra A, Waall Malefyt R de, Viera P, Mosmann TR (1993) Interleukin-10. Annu Rev Immunol 11: 165

    Google Scholar 

  25. Nakamura K, Okamura H, Wada M, Nagata K, Tamura T (1989) Endotoxin-induced serum factor that stimulates gamma interferon production. Infect Immun 57:590

    Google Scholar 

  26. Neurath MF, Fuss I, Kelsall BL, Stuber E, Strober W (1995) Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med 182:128

    Google Scholar 

  27. Nicholson LB, Greer JM, Sobel RA, Lees MB, Kuchroo VK (1995) An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis. Immunity 3: 397

    Google Scholar 

  28. Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Nukada Y, Hattori K, Akita K, Namba M, Tanabe F, Konishi K, Fukuda S, Kurimoto M (1995) Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 378: 88

    Google Scholar 

  29. Ota K, Matsui M, Milford EL, Mackin GA, Weiner HL, Haller DA (1990) T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 346: 183

    Google Scholar 

  30. Pette M, Fujita K, Kitze B, Whitaker JN, Albert E, Kappos L, Wekerle H (1990) Myelin protein-specific T lymphocyte lines from MS patients and healthy individuals. Neurology 40: 1770

    Google Scholar 

  31. 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

    Google Scholar 

  32. Robinson D, Shibuya K, Mui A, Zonin F, Murphy E, Sana T, Hartley SB, Menon S, Kastelein R, Bazan F, O'Garra A (1997) IGIF does not drive Th1 development but synergizes with IL-12 for interferon-gamma production and activates IRAK and NFkappaB. Immunity 7: 571

    Google Scholar 

  33. Rocken M, Urban J, Shevach EM (1994) Antigen-specific activation, tolerization, and reactivation of the interleukin 4 pathway in vivo. J Exp Med 179:1885

    Google Scholar 

  34. Rott O, Fleischer B, Cash E (1994) Interleukin-10 prevents experimental autoimmune encephalomyelitis in rats. Eur J Immunol 24: 1434

    Google Scholar 

  35. Scharton-Kersten TM, Wynn TA, Denkers EY, Bala S, Grunvald E, Hierny S, Gazzinelli RT, Sher A (1996) In the absence of endogenous IFN-γ, mice develop unimpaired IL-12 responses toToxoplasma gondii while failing to control acute infection. J Immunol 157:4045

    Google Scholar 

  36. Segal BM, Dwyer BK, Shevach EM (1998) An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J Exp Med 187: 537

    Google Scholar 

  37. Segal BM, Klinman DM, Shevach EM (1997) Microbial products induce autoimmune disease by an IL-12-dependent pathway. J Immunol 158: 5087

    Google Scholar 

  38. Segal BM, Shevach EM (1996) IL-12 unmasks latent autoimmune disease in resistant mice. J Exp Med 184:771

    Google Scholar 

  39. Shaw MK, Lorens JB, Dhawan A, DalCanto R, Tse HY, Tran AB, Bonpane C, Eswaran SL, Brocke S, Sarvemick N, Steinman L, Nolan GP, Fathman CG (1997) Local delivery of interleukin 4 by retrovirus-transduced T lymphocytes ameliorates experimental autoimmune encephalomyelitis. J Exp Med 185:1711

    Google Scholar 

  40. Sher A, Coffman RL (1992) Regulation of immunity to parasites by T cells and T cell derived-cytokines. Annu Rev Immunol 10: 385

    Google Scholar 

  41. Szabo SJ, Dighe AS, Gubler U, Murphy KM (1997) Regulation of the interleukin (IL)-12R b2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J Exp Med 185: 817

    Google Scholar 

  42. Szabo SJ, Jacobson NG, Dighe AS, Gubler U, Murphy KM (1995) Developmental commitment to the Th2 lineage by extinction of IL-12 signaling. Immunity 6: 665

    Google Scholar 

  43. Trembleau S, Penna G, Bosi E, Mortara A, Gately MK, Adorini L (1995) Interleukin 12 induces T helper 1 cells and accelerates autoimmune diabetes in NOD mice. J Exp Med 181:817

    Google Scholar 

  44. Tripp CS, Gately MK, Hakimi J, Ling P, Unanue ER (1994) Neutralization of IL-12 decreases resistance toListeria in SCID and CB.17 mice. Reversal by IFN-gamma. J Immunol 152: 1883

    Google Scholar 

  45. 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

    Google Scholar 

  46. Wraith DC, Smilek DE, Mitchell DJ, Steinman L, McDevitt HO (1989) Antigen recognition in autoimmune encephalomyelitis and the potential for peptide-mediated immunotherapy. Cell 59:247

    Google Scholar 

  47. Wraith DC, Bruhn B, Fairchild PJ (1992) Cross-reactive antigen recognition by an encephalitogenic T cell receptor: implications for T cell biology and autoimmunity. J Immunol 149: 3765

    Google Scholar 

  48. Xu D, Chan WL, Leung BP, Hunter D, Schulz K, Carter RW, McInnes IB, Robinson JH, Liew FY (1998) Selective expression and functions of interleukin 18 receptor on T helper (Th) type 1 but not Th2 cells. J Exp Med 188: 1485

    Google Scholar 

  49. Yoshimoto T, Takeda K, Tanaka T, Ohkusu K, Kashiwamura S, Okamura H, Akira S, Nakanishi K (1998) IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells; and B cells: synergism with IL-18 for IFN-gamma production. J Immunol 161: 3400

    Google Scholar 

  50. Zamvil SS, Steinman L (1990) The T lymphocyte in experimental allergic encephalomyelitis. Annu Rev Immunol 8:579

    Google Scholar 

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Authors and Affiliations

  1. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Blg. 10, RM11N315, 20892, Bethesda, MD, USA

    Ethan M. Shevach & Benjamin M. Segal

  2. Howard Hughes Medical Institute Research Scholars Program, 20892, Bethesda, MD, USA

    John T. Chang

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Shevach, E.M., Chang, J.T. & Segal, B.M. The critical role of IL-12 and the IL-12Rβ2 subunit in the generation of pathogenic autoreactive Th1 cells. Springer Semin Immunopathol 21, 249–262 (1999). https://doi.org/10.1007/BF00812256

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