Skip to main content
SpringerLink
Log in
Book cover

Experimental Models of Multiple Sclerosis pp 201–243Cite as

T Lymphocytes in EAE

Insights into the development and control of the autoreactive T cell

  • Chapter

  • 2206 Accesses

Abstract

The EAE lesion is initiated by CD4+ T cells. Although this statement still holds, recent work has shown that CD8+ T cells and possibly γδ T cells can also contribute to pathology. The recovery phase of the disease poses more of a challenge with the potential for various regulatory T cell populations to halt the pathology. We know a good deal about the fine-specificity of T cell recognition of epitopes derived from myelin autoantigens. This, coupled with technological refinements in cellular immunology, is allowing us to ask important questions about the generation and control of the autoreactive T cell repertoire. This information also provides the basis for models of how these cells become activated and for advances in antigen-specific therapeutic intervention.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Rivers, T. M., Sprunt, D. H. & Berry, G. P. Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J. Exp. Med. 58, 39–53 (1933).

    Google Scholar 

  2. Martin, R. & McFarland, H. F. Immunological Aspects of Experimental Allergic Encephalomyelitis and Multiple-Sclerosis. Crit. Rev. Clin. Lab. Sci. 32, 121–182 (1995).

    PubMed  CAS  Google Scholar 

  3. Kabat, E. A., Wolf, A. & Bezer, A. E. The rapid production of acute disseminated encephalomyelitis in rhesus monkeys by injection of heterozygous and homologous brain tisuue in adjuvants. J. Exp. Med. 85, 117–130 (1947).

    Google Scholar 

  4. Paterson, P. Y. Transfer of allergic encephalomyelitis in rats by means of lymph node cells. J. Exp. Med. 111, 119–135 (1960).

    PubMed  CAS  Google Scholar 

  5. Arnason, B. G., Jankovic, B. D., Waksman, B. H. & Wennerston, C. Role of the thymus in immune reactions in rats. II. Suppressive effect of thymectomy at birth on reactions of delayed (cellular) hypersensitivity and the circulating small lymphocyte. J. Exp. Med. 116, 177–186 (1962).

    PubMed  CAS  Google Scholar 

  6. Pettinelli, C. B. & McFarlin, D. E. 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. 127, 1420–3 (1981).

    PubMed  CAS  Google Scholar 

  7. Brostoff, S. W. & Mason, D. W. Experimental allergic encephalomyelitis: successful treatment in vivo with a monoclonal antibody that recognizes T helper cells. J. Immunol. 133, 1938–42 (1984).

    PubMed  CAS  Google Scholar 

  8. Zamvil, S. et al. T-cell clones specific for myelin basic protein induce chronic relapsing paralysis and demyelination. Nature 317, 355–8 (1985).

    PubMed  CAS  Google Scholar 

  9. Karandikar, N. J., Vanderlugt, C. L., Bluestone, J. A. & Miller, S. D. Targeting the B7/CD28:CTLA-4 costimulatory system in CNS autoimmune disease. J. Neuroimmunol. 89, 10–8 (1998).

    PubMed  CAS  Google Scholar 

  10. Grewal, I. S. et al. Requirement for CD40 ligand in costimulation induction, T cell activation, and experimental allergic encephalomyelitis. Science 273, 1864–7 (1996).

    PubMed  CAS  Google Scholar 

  11. Howard, L. M. et al. Mechanisms of immunotherapeutic intervention by anti-CD40L (CD154) antibody in an animal model of multiple sclerosis. J. Clin. Invest. 103, 281–90 (1999).

    PubMed  CAS  Google Scholar 

  12. Ndhlovu, L. C., Ishii, N., Murata, K., Sato, T. & Sugamura, K. Critical involvement of OX40 ligand signals in the T cell priming events during experimental autoimmune encephalomyelitis. J. Immunol. 167, 2991–9 (2001).

    PubMed  CAS  Google Scholar 

  13. Weinberg, A. D., Wegmann, K. W., Funatake, C. & Whitham, R. H. Blocking OX-40/OX-40 ligand interaction in vitro and in vivo leads to decreased T cell function and amelioration of experimental allergic encephalomyelitis. J. Immunol. 162, 1818–26 (1999).

    PubMed  CAS  Google Scholar 

  14. Dong, C. et al. ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 409, 97–101 (2001).

    PubMed  CAS  Google Scholar 

  15. Dijkstra, C. D., De Groot, C. J. & Huitinga, I. The role of macrophages in demyelination. J. Neuroimmunol. 40, 183–8 (1992).

    PubMed  CAS  Google Scholar 

  16. Bauer, J. et al. The role of macrophages, perivascular cells, and microglial cells in the pathogenesis of experimental autoimmune encephalomyelitis. Glia 15, 437–46 (1995).

    PubMed  CAS  Google Scholar 

  17. Stefferl, A., Brehm, U. & Linington, C. The myelin oligodendrocyte glycoprotein (MOG): a model for antibody-mediated demyelination in experimental autoimmune encephalomyelitis and multiple sclerosis. J. Neur. Trans., 123–33 (2000).

    Google Scholar 

  18. Anderton, S. M. & Wraith, D. C. Hierarchy in the ability of T cell epitopes to induce peripheral tolerance to antigens from myelin. Eur. J. Immunol. 28, 1251–61 (1998).

    PubMed  CAS  Google Scholar 

  19. Deber, C. M. & Reynolds, S. J. Central nervous system myelin: structure, function, and pathology. Cell. Biochem. 24, 113–34 (1991).

    CAS  Google Scholar 

  20. Greer, J. M. & Lees, M. B. Myelin proteolipid protein-the first 50 years. Int. J. Biochem. 34, 211–5 (2002).

    CAS  Google Scholar 

  21. della Gaspera, B., Pham-Dinh, D., Roussel, G., Nussbaum, J. L. & Dautigny, A. Membrane topology of the myelin/oligodendrocyte glycoprotein. Eur. J. Biochem. 258, 478–84 (1998).

    PubMed  Google Scholar 

  22. Kies, M. W., Murphy, J. B. & Alvord, E. C. Fractionation of guinea pig proteins with encephalitogenic activity. Fed. Proc. 19, 207 (1960).

    Google Scholar 

  23. Williams, R. M., Lees, M. B., Cambi, F. & Macklin, W. B. Chronic experimental allergic encephalomyelitis induced in rabbits with bovine white matter proteolipid apoprotein. J. Neuropath. Exp. Neurol. 41, 508–21 (1982).

    PubMed  CAS  Google Scholar 

  24. Adelmann, M. et al. The N-terminal domain of the myelin oligodendrocyte glycoprotein (MOG) induces acute demyelinating experimental autoimmune encephalomyelitis in the Lewis rat. J. Neuroimmunol. 63, 17–27 (1995).

    PubMed  CAS  Google Scholar 

  25. Tuohy, V. K., Lu, Z., Sobel, R. A., Laursen, R. A. & Lees, M. B. Identification of an encephalitogenic determinant of myelin proteolipid protein for SJL mice. J. Immunol. 142, 1523–7 (1989).

    PubMed  CAS  Google Scholar 

  26. Amor, S., Baker, D., Groome, N. & Turk, J. L. Identification of a major encephalitogenic epitope of proteolipid protein (residues 56-70) for the induction of experimental allergic encephalomyelitis in Biozzi AB/H and nonobese diabetic mice. J. Immunol. 150, 5666–72 (1993).

    PubMed  CAS  Google Scholar 

  27. Amor, S. et al. Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice. J. Immunol. 153, 4349–56 (1994).

    PubMed  CAS  Google Scholar 

  28. Mendel, I., Derosbo, N. K. & Bennun, A. A Myelin Oligodendrocyte Glycoprotein Peptide Induces Typical Chronic Experimental Autoimmune Encephalomyelitis in H-2(B) Mice-Fine Specificity and T-Cell Receptor V-Beta Expression of Encephalitogenic T-Cells. Eur. J. Immunol. 25, 1951–1959 (1995).

    PubMed  CAS  Google Scholar 

  29. Bates, I. R. et al. Characterization of a recombinant murine 18.5-kDa myelin basic protein. Prot. Exp. Purif. 20, 285–99 (2000).

    CAS  Google Scholar 

  30. Pham-Dinh, D. et al. Characterization and expression of the cDNA coding for the human myelin/oligodendrocyte glycoprotein. J. Neurochem. 63, 2353–6 (1994).

    PubMed  CAS  Google Scholar 

  31. Watts, C. Capture and processing of exogenous antigens for presentation on MHC molecules. Annu. Rev. Immunol. 15, 821–50 (1997).

    PubMed  CAS  Google Scholar 

  32. Eylar, E. H., Caccam, J., Jackson, J. J., Westall, F. C. & Robinson, A. B. Experimental allergic encephalomyelitis: synthesis of disease-inducing site of the basic protein. Science 168, 1220–3 (1970).

    PubMed  CAS  Google Scholar 

  33. Zamvil, S. S. et al. T-cell epitope of the autoantigen myelin basic protein that induces encephalomyelitis. Nature 324, 258–60 (1986).

    PubMed  CAS  Google Scholar 

  34. Chou, C. H., Chou, F. C., Kowalski, T. J., Shapira, R. & Kibler, R. F. The major site of guinea-pig myelin basic protein encephalitogenic in Lewis rats. J. Neurochem. 28, 115–9(1977).

    PubMed  CAS  Google Scholar 

  35. Westall, F. C., Robinson, A. B., Caccam, J., Jackson, J. & Ylar, E. H. Essential chemical requirements for induction of allergic encephalomyelitis. Nature 229, 22–4 (1971).

    PubMed  CAS  Google Scholar 

  36. Evavold, B. D. & Allen, P. M. Separation of II-4 Production from Th-Cell Proliferation by an Altered T-Cell Receptor Ligand. Science 252, 1308–1310 (1991).

    PubMed  CAS  Google Scholar 

  37. Karkhanis, Y. D., Carlo, D. J., Brostoff, S. W. & Eylar, E. H. Allergic encephalomyelitis. Isolation of an encephalitogenic peptide active in the monkey. J. Biol. Chem. 250, 1718–22 (1975).

    PubMed  CAS  Google Scholar 

  38. Offner, H. et al. T cell determinants of myelin basic protein include a unique encephalitogenic I-E-restricted epitope for Lewis rats. J. Exp. Med. 170, 355–67 (1989).

    PubMed  CAS  Google Scholar 

  39. Sakai, K. et al. Characterization of a major encephalitogenic T cell epitope in SJL/J mice with synthetic oligopeptides of myelin basic protein. J. Neuroimmunol. 19, 21–32 (1988).

    PubMed  CAS  Google Scholar 

  40. Chou, Y. K., Vandenbark, A. A., Jones, R. E., Hashim, G. & Offner, H. Selection of encephalitogenic rat T-lymphocyte clones recognizing an immunodominant epitope on myelin basic protein. J. Neurosci. Res. 22, 181–7 (1989).

    PubMed  CAS  Google Scholar 

  41. Martin, R. et al. Fine specificity and HLA restriction of myelin basic protein-specific cytotoxic T cell lines from multiple sclerosis patients and healthy individuals. J. Immunol. 145, 540–8 (1990).

    PubMed  CAS  Google Scholar 

  42. Ota, K. et al. T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 346, 183–7 (1990).

    PubMed  CAS  Google Scholar 

  43. Lafaille, J. J., Nagashima, K., Katsuki, M. & Tonegawa, S. High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice. Cell 78, 399–408 (1994).

    PubMed  CAS  Google Scholar 

  44. Goverman, J. et al. Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell 72, 551–60 (1993).

    PubMed  CAS  Google Scholar 

  45. Liu, G. Y. et al. Low avidity recognition of self-antigen by T cells permits escape from central tolerance. Immunity 3, 407–15 (1995).

    PubMed  CAS  Google Scholar 

  46. Kissler, S., Anderton, S. M. & Wraith, D. C. Antigen-presenting cell activation: a link between infection and autoimmunity? J. Autoimmun. 16, 303–8 (2001).

    PubMed  CAS  Google Scholar 

  47. Waldner, H., Whitters, M. J., Sobel, R. A., Collins, M. & Kuchroo, V. K. Fulminant spontaneous autoimmunity of the central nervous system in mice transgenic for the myelin proteolipid protein-specific T cell receptor. Proc. Natl. Acad. Sci. USA 97, 3412–7 (2000).

    PubMed  CAS  Google Scholar 

  48. Madsen, L. S. et al. A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor. Nature Gen. 23, 343–7 (1999).

    CAS  Google Scholar 

  49. Klenerman, P., Cerundolo, V. & Dunbar, P. R. Tracking T cells with tetramers: new tales from new tools. Nat. Rev. Immunol. 2, 263–72 (2002).

    PubMed  CAS  Google Scholar 

  50. Radu, C. G., Anderton, S. M., Firan, M., Wraith, D. C. & Ward, E. S. Detection of autoreactive T cells in H-2u mice using peptide-MHC multimers. Int. Immunol. 12, 1553–60 (2000).

    PubMed  CAS  Google Scholar 

  51. Anderton, S. M., Radu, C. G., Lowrey, P. A., Ward, E. S. & Wraith, D. C. Negative selection during the peripheral immune response to antigen. J. Exp. Med 193, 1–11 (2001).

    PubMed  CAS  Google Scholar 

  52. Targoni, O. S. et al. Frequencies of neuroantigen-specific T cells in the central nervous system versus the immune periphery during the course of experimental allergic encephalomyelitis. J. Immunol. 166, 4757–64 (2001).

    PubMed  CAS  Google Scholar 

  53. Flugel, A., Willem, M., Berkowicz, T. & Wekerle, H. Gene transfer into CD4+ T lymphocytes: green fluorescent protein-engineered, encephalitogenic T cells illuminate brain autoimmune responses. Nature Med. 5, 843–7 (1999).

    PubMed  CAS  Google Scholar 

  54. Flugel, A. et al. Migratory activity and functional changes of green fluorescent effector cells before and during experimental autoimmune encephalomyelitis. Immunity 14, 547–60 (2001).

    PubMed  CAS  Google Scholar 

  55. Elenkov, I. J. & Chrousos, G. P. Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity. Ann. NY. Acad. Sci. 966, 290–303 (2002).

    PubMed  CAS  Google Scholar 

  56. Mosmann, T. R. & Coffman, R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–73 (1989).

    PubMed  CAS  Google Scholar 

  57. Kuchroo, V. K. et al. Cytokines and adhesion molecules contribute to the ability of myelin proteolipid protein-specific T cell clones to mediate experimental allergic encephalomyelitis. J. Immunol. 151, 4371–82 (1993).

    PubMed  CAS  Google Scholar 

  58. Heeger, P. S. et al. Revisiting tolerance induced by autoantigen in incomplete Freund’s adjuvant. J. Immunol. 164, 5771–81 (2000).

    PubMed  CAS  Google Scholar 

  59. Macatonia, S. E. et al. Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J. Immunol. 154, 5071–9 (1995).

    PubMed  CAS  Google Scholar 

  60. Seder, R. A., Gazzinelli, R., Sher, A. & Paul, W. E. Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon gamma production and diminishes interleukin 4 inhibition of such priming. Proc. Natl. Acad. Sci. USA 90, 10188–92 (1993).

    PubMed  CAS  Google Scholar 

  61. Halpern, M. D., Kurlander, R. J. & Pisetsky, D. S. Bacterial DNA induces murine interferon-gamma production by stimulation of interleukin-12 and tumor necrosis factor-alpha. Cell. Immunol. 167, 72–8 (1996).

    PubMed  CAS  Google Scholar 

  62. Klinman, D. M., Yi, A. K., Beaucage, S. L., Conover, J. & Krieg, A. M. CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon gamma. Proc. Natl. Acad. Sci. USA 93, 2879–83 (1996).

    PubMed  CAS  Google Scholar 

  63. Segal, B. M., Chang, J. T. & Shevach, E. M. CpG oligonucleotides are potent adjuvants for the activation of autoreactive encephalitogenic T cells in vivo. J. Immunol. 164, 5683–8 (2000).

    PubMed  CAS  Google Scholar 

  64. Ichikawa, H. T., Williams, L. P. & Segal, B. M. Activation of APCs through CD40 or Toll-like receptor 9 overcomes tolerance and precipitates autoimmune disease. J. Immunol. 169, 2781–7 (2002).

    PubMed  CAS  Google Scholar 

  65. Leonard, J. P., Waldburger, K. E. & Goldman, S. J. Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J. Exp. Med 181,381–6(1995).

    PubMed  CAS  Google Scholar 

  66. Segal, B. M., Dwyer, B. K. & Shevach, E. M. An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J. Exp. Med 187, 537–46 (1998).

    PubMed  CAS  Google Scholar 

  67. Dore-Duffy, P., Balabanov, R., Rafols, J. & Swanborg, R. H. Recovery phase of acute experimental autoimmune encephalomyelitis in rats corresponds to development of endothelial cell unresponsiveness to interferon gamma activation. J. Neurosci. Res. 44, 223–34 (1996).

    PubMed  CAS  Google Scholar 

  68. Duong, T. T., Finkelman, F. D., Singh, B. & Strejan, G. H. Effect of anti-interferon-gamma monoclonal antibody treatment on the development of experimental allergic encephalomyelitis in resistant mouse strains. J. Neuroimmunol. 53, 101–7 (1994).

    PubMed  CAS  Google Scholar 

  69. Lublin, F. D. et al. Monoclonal anti-gamma interferon antibodies enhance experimental allergic encephalomyelitis. Autoimmunity 16, 267–74 (1993).

    PubMed  CAS  Google Scholar 

  70. Ferber, I. A. et al. Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J. Immunol. 156, 5–7 (1996).

    PubMed  CAS  Google Scholar 

  71. Krakowski, M. & Owens, T. Interferon-gamma confers resistance to experimental allergic encephalomyelitis. Eur. J. Immunol. 26, 1641–6 (1996).

    PubMed  CAS  Google Scholar 

  72. Willenborg, D. O., Fordham, S., Bernard, C. C., Cowden, W. B. & Ramshaw, I. A. IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J. Immunol. 157, 3223–7 (1996).

    PubMed  CAS  Google Scholar 

  73. Selmaj, K. & Raine, C. S. Tumor necrosis factor mediates myelin damage in organotypic cultures of nervous tissue. Ann. NY. Acad. Sci. 540, 568–70 (1988).

    PubMed  CAS  Google Scholar 

  74. Selmaj, K., Raine, C. S., Farooq, M., Norton, W. T. & Brosnan, C. F. Cytokine cytotoxicity against oligodendrocytes. Apoptosis induced by lymphotoxin. J. Immunol. 147, 1522–9(1991).

    PubMed  CAS  Google Scholar 

  75. Merrill, J. E., Ignarro, L. J., Sherman, M. P., Melinek, J. & Lane, T. E. Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. J. Immunol. 151, 2132–41 (1993).

    PubMed  CAS  Google Scholar 

  76. Ruddle, N. H. et al. An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J. Exp. Med 172, 1193–200 (1990).

    PubMed  CAS  Google Scholar 

  77. Suen, W. E., Bergman, C. M., Hjelmstrom, P. & Ruddle, N. H. A critical role for lymphotoxin in experimental allergic encephalomyelitis. J. Exp. Med 186, 1233–40 (1997).

    PubMed  CAS  Google Scholar 

  78. Frei, K. et al. Tumor necrosis factor alpha and lymphotoxin alpha are not required for induction of acute experimental autoimmune encephalomyelitis. J. Exp. Med 185, 2177–82 (1997).

    PubMed  CAS  Google Scholar 

  79. Genain, C. P. et al. Late complications of immune deviation therapy in a nonhuman primate. Science 274, 2054–7 (1996).

    PubMed  CAS  Google Scholar 

  80. Pedotti, R. et al. An unexpected version of horror autotoxicus: anaphylactic shock to a self-peptide. Nature Immunol 2, 216–22 (2001).

    CAS  Google Scholar 

  81. Lafaille, J. J. et al. Myelin basic protein-specific T helper 2 (Th2) cells cause experimental autoimmune encephalomyelitis in immunodeficient hosts rather than protect them from the disease. J. Exp. Med 186, 307–12 (1997).

    PubMed  CAS  Google Scholar 

  82. Heeger, P. S. et al. Revisiting tolerance induced by autoantigen in incomplete Freund’s adjuvant. J. Immunol. 164, 5771–5781 (2000).

    PubMed  CAS  Google Scholar 

  83. Gaur, A. et al. Amelioration of relapsing experimental autoimmune encephalomyelitis with altered myelin basic protein peptides involves different cellular mechanisms. J. Neuroimmunol. 74, 149–58 (1997).

    PubMed  CAS  Google Scholar 

  84. Di Rosa, F. et al. Lack of Th2 cytokine increase during spontaneous remission of experimental allergic encephalomyelitis. Eur. J. Immunol. 28, 3893–903 (1998).

    PubMed  Google Scholar 

  85. Kennedy, M. K., Torrance, D. S., Picha, K. S. & Mohler, K. M. Analysis of cytokine mRNA expression in the central nervous system of mice with experimental autoimmune encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery. J. Immunol. 149, 2496–505 (1992).

    PubMed  CAS  Google Scholar 

  86. Khoury, S. J., Hancock, W. W. & Weiner, H. L. Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin 4, and prostaglandin E expression in the brain. J. Exp. Med 176, 1355–64 (1992).

    PubMed  CAS  Google Scholar 

  87. Racke, M. K. et al. Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. J. Exp. Med 180, 1961–6 (1994).

    PubMed  CAS  Google Scholar 

  88. Shaw, M. K. et al. Local delivery of interleukin 4 by retrovirus-transduced T lymphocytes ameliorates experimental autoimmune encephalomyelitis. J. Exp. Med 185, 1711–4(1997).

    PubMed  CAS  Google Scholar 

  89. Liblau, R., Steinman, L. & Brocke, S. Experimental autoimmune encephalomyelitis in IL-4-deficient mice. Int. Immunol. 9, 799–803 (1997).

    PubMed  CAS  Google Scholar 

  90. Bettelli, E. et al. IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10-and IL-4-deficient and transgenic mice. J. Immunol. 161, 3299–306 (1998).

    PubMed  CAS  Google Scholar 

  91. Samoilova, E. B., Horton, J. L. & Chen, Y. Acceleration of experimental autoimmune encephalomyelitis in interleukin-10-deficient mice: roles of interleukin-10 in disease progression and recovery. Cell. Immunol. 188, 118–24 (1998).

    PubMed  CAS  Google Scholar 

  92. Cua, D. J., Groux, H., Hinton, D. R., Stohlman, S. A. & Coffman, R. L. Transgenic interleukin 10 prevents induction of experimental autoimmune encephalomyelitis. J. Exp. Med 189, 1005–10 (1999).

    PubMed  CAS  Google Scholar 

  93. Xiao, B. G., Bai, X. F., Zhang, G. X. & Link, H. Suppression of acute and protracted-relapsing experimental allergic encephalomyelitis by nasal administration of low-dose IL-10 in rats. J. Neuroimmunol. 84, 230–7 (1998).

    PubMed  CAS  Google Scholar 

  94. Croxford, J. L., Feldmann, M., Chernajovsky, Y. & Baker, D. Different therapeutic outcomes in experimental allergic encephalomyelitis dependent upon the mode of delivery of IL-10: a comparison of the effects of protein, adenoviral or retroviral IL-10 delivery into the central nervous system. J. Immunol. 166, 4124–30 (2001).

    PubMed  CAS  Google Scholar 

  95. Cannella, B., Gao, Y. L., Brosnan, C. & Raine, C. S. IL-10 fails to abrogate experimental autoimmune encephalomyelitis. J. Neurosci. Res. 45, 735–46 (1996).

    PubMed  CAS  Google Scholar 

  96. Rott, O., Fleischer, B. & Cash, E. Interleukin-10 prevents experimental allergic encephalomyelitis in rats. Eur. J. Immunol. 24, 1434–40 (1994).

    PubMed  CAS  Google Scholar 

  97. Mathisen, P. M., Yu, M., Johnson, J. M., Drazba, J. A. & Tuohy, V. K. Treatment of experimental autoimmune encephalomyelitis with genetically modified memory T cells. J. Exp. Med 186, 159–64 (1997).

    PubMed  CAS  Google Scholar 

  98. Nagelkerken, L., Blauw, B. & Tielemans, M. IL-4 abrogates the inhibitory effect of IL-10 on the development of experimental allergic encephalomyelitis in SJL mice. Int. Immunol. 9, 1243–51 (1997).

    PubMed  CAS  Google Scholar 

  99. Racke, M. K. et al. Prevention and treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-beta 1. J. Immunol. 146, 3012–7(1991).

    PubMed  CAS  Google Scholar 

  100. Kuruvilla, A. P. et al. Protective effect of transforming growth factor beta 1 on experimental autoimmune diseases in mice. Proc. Natl. Acad. Sci. USA 88, 2918–21 (1991).

    PubMed  CAS  Google Scholar 

  101. Kehrl, J. H. et al. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J. Exp. Med 163, 1037–50(1986).

    PubMed  CAS  Google Scholar 

  102. Espevik, T. et al. Inhibition of cytokine production by cyclosporin A and transforming growth factor beta. J. Exp. Med 166, 571–6 (1987).

    PubMed  CAS  Google Scholar 

  103. Tsunawaki, S., Sporn, M., Ding, A. & Nathan, C. Deactivation of macrophages by transforming growth factor-beta. Nature 334, 260–2 (1988).

    PubMed  CAS  Google Scholar 

  104. Moore, K. W., de Waal Malefyt, R., Coffman, R. L. & O’Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).

    PubMed  CAS  Google Scholar 

  105. Menges, M. et al. Repetitive injections of dendritic cells matured with tumor necrosis factor alpha induce antigen-specific protection of mice from autoimmunity. J. Exp. Med 195, 15–21 (2002).

    PubMed  CAS  Google Scholar 

  106. Steinman, L. Myelin-specific CD8 T cells in the pathogenesis of experimental allergic encephalitis and multiple sclerosis. J. Exp. Med 194, F27–30 (2001).

    PubMed  CAS  Google Scholar 

  107. Traugott, U., Reinherz, E. L. & Raine, C. S. Multiple sclerosis: distribution of T cell subsets within active chronic lesions. Science 219, 308–10 (1983).

    PubMed  CAS  Google Scholar 

  108. Hauser, S. L. et al. Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions. Ann. Neurol. 19, 578–87 (1986).

    PubMed  CAS  Google Scholar 

  109. Sriram, S., Solomon, D., Rouse, R. V. & Steinman, L. Identification of T cell subsets and B lymphocytes in mouse brain experimental allergic encephalitis lesions. J. Immunol. 129, 1649–51 (1982).

    PubMed  CAS  Google Scholar 

  110. Sun, D. et al. Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL/6 mice. J. Immunol. 166, 7579–87 (2001).

    PubMed  CAS  Google Scholar 

  111. Huseby, E. S. et al. A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis. J. Exp. Med 194, 669–76 (2001).

    PubMed  CAS  Google Scholar 

  112. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurol. 53, 457–65 (1999).

    Google Scholar 

  113. Panitch, H. S., Hirsch, R. L., Schindler, J. & Johnson, K. P. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurol. 37, 1097–102 (1987).

    CAS  Google Scholar 

  114. Matsumoto, Y. et al. Role of natural killer cells and TCR gamma delta T cells in acute autoimmune encephalomyelitis. Eur. J. Immunol. 28, 1681–8 (1998).

    PubMed  CAS  Google Scholar 

  115. Clark, R. B. & Lingenheld, E. G. Adoptively transferred EAE in gamma delta T cell-knockout mice. J. Autoimmun. 11, 105–10 (1998).

    PubMed  CAS  Google Scholar 

  116. Olive, C. Gamma delta T cell receptor variable region usage during the development of experimental allergic encephalomyelitis. J. Neuroimmunol. 62, 1–7 (1995)

    PubMed  CAS  Google Scholar 

  117. Selmaj, K., Brosnan, C. F. & Raine, C. S. Colocalization of lymphocytes bearing gamma delta T-cell receptor and heat shock protein hsp65+ oligodendrocytes in multiple sclerosis. Proc. Natl. Acad. Sci. USA 88, 6452–6 (1991).

    PubMed  CAS  Google Scholar 

  118. Wucherpfennig, K. W. et al. Gamma delta T-cell receptor repertoire in acute multiple sclerosis lesions. Proc. Natl. Acad. Sci. USA 89, 4588–92 (1992).

    PubMed  CAS  Google Scholar 

  119. Rajan, A. J., Gao, Y. L., Raine, C. S. & Brosnan, C. F. A pathogenic role for gamma delta T cells in relapsing-remitting experimental allergic encephalomyelitis in the SJL mouse. J. Immunol. 157, 941–9 (1996).

    PubMed  CAS  Google Scholar 

  120. Kobayashi, Y. et al. Aggravation of murine experimental allergic encephalomyelitis by administration of T-cell receptor gammadelta-specific antibody. J. Neuroimmunol. 73, 169–74(1997).

    PubMed  CAS  Google Scholar 

  121. Jensen, M. A., Dayal, A. & Arnason, B. G. Cytokine secretion by deltagamma and alphabeta T cells in monophasic experimental autoimmune encephalomyelitis. J. Autoimmun. 12, 73–80 (1999).

    PubMed  CAS  Google Scholar 

  122. Gao, Y. L., Rajan, A. J., Raine, C. S. & Brosnan, C. F. gammadelta T cells express activation markers in the central nervous system of mice with chronic-relapsing experimental autoimmune encephalomyelitis. J. Autoimmun. 17, 261–71 (2001).

    PubMed  CAS  Google Scholar 

  123. Rajan, A. J., Klein, J. D. & Brosnan, C. F. The effect of gammadelta T cell depletion on cytokine gene expression in experimental allergic encephalomyelitis. J. Immunol. 160, 5955–62 (1998).

    PubMed  CAS  Google Scholar 

  124. Rajan, A. J., Asensio, V. C., Campbell, I. L. & Brosnan, C. F. Experimental autoimmune encephalomyelitis on the SJL mouse: effect of gamma delta T cell depletion on chemokine and chemokine receptor expression in the central nervous system. J. Immunol. 164, 2120–30 (2000).

    PubMed  CAS  Google Scholar 

  125. Spahn, T. W., Issazadah, S., Salvin, A. J. & Weiner, H. L. Decreased severity of myelin oligodendrocyte glycoprotein peptide 33-35-induced experimental autoimmune encephalomyelitis in mice with a disrupted TCR delta chain gene. Eur. J. Immunol. 29, 4060–71 (1999).

    PubMed  CAS  Google Scholar 

  126. Sakaguchi, S. et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol. Rev. 182, 18–32 (2001).

    PubMed  CAS  Google Scholar 

  127. Shevach, E. M. CD4+ CD25+ suppressor T cells: more questions than answers. Nat. Rev. Immunol. 2, 389–400 (2002).

    PubMed  CAS  Google Scholar 

  128. Maloy, K. J. & Powrie, F. Regulatory T cells in the control of immune pathology. Nature Immunol. 2, 816–822 (2001).

    CAS  Google Scholar 

  129. Asano, M., Toda, M., Sakaguchi, N. & Sakaguchi, S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J. Exp. Med 184, 387–96 (1996).

    PubMed  CAS  Google Scholar 

  130. 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. 155, 1151–64 (1995).

    PubMed  CAS  Google Scholar 

  131. Fowell, D. & Mason, D. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential. J. Exp. Med 177, 627–36 (1993).

    PubMed  CAS  Google Scholar 

  132. Powrie, F. et al. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1, 553–62 (1994).

    PubMed  CAS  Google Scholar 

  133. Powrie, F. & Mason, D. OX-22high CD4+ T cells induce wasting disease with multiple organ pathology: prevention by the OX-221ow subset. J. Exp. Med 172, 1701–8 (1990).

    PubMed  CAS  Google Scholar 

  134. Papiernik, M., de Moraes, M. L., Pontoux, C., Vasseur, F. & Penit, C. Regulatory CD4 T cells: expression of IL-2R alpha chain, resistance to clonal deletion and IL-2 dependency. Int. Immunol. 10, 371–8 (1998).

    PubMed  CAS  Google Scholar 

  135. Maloy, K. J. & Powrie, F. Regulatory T cells in the control of immune pathology. Nature Immunol. 2, 816–22 (2001).

    CAS  Google Scholar 

  136. Asseman, C., Mauze, S., Leach, M. W., Coffman, R. L. & Powrie, F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med 190, 995–1004 (1999).

    PubMed  CAS  Google Scholar 

  137. Powrie, F., Carlino, J., Leach, M. W., Mauze, S. & Coffman, R. L. A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J. Exp. Med 183, 2669–74 (1996).

    PubMed  CAS  Google Scholar 

  138. Olivares-Villagomez, D., Wang, Y. & Lafaille, J. J. Regulatory CD4(+) T cells expressing endogenous T cell receptor chains protect myelin basic protein-specific transgenic mice from spontaneous autoimmune encephalomyelitis. J. Exp. Med 188, 1883–94 (1998).

    PubMed  CAS  Google Scholar 

  139. Olivares-Villagomez, D., Wensky, A. K., Wang, Y. & Lafaille, J. J. Repertoire requirements of CD4+ T cells that prevent spontaneous autoimmune encephalomyelitis. J. Immunol. 164, 5499–507 (2000).

    PubMed  CAS  Google Scholar 

  140. Kohm, A. P., Carpentier, P. A., Anger, H. A. & Miller, S. D. Cutting edge: CD4+CD25+ Regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J. Immunol. 169, 4712–4716 (2002).

    PubMed  CAS  Google Scholar 

  141. Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–42 (1997).

    PubMed  CAS  Google Scholar 

  142. Barrat, F. J. 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 195, 603–16 (2002).

    PubMed  CAS  Google Scholar 

  143. McGuirk, P., McCann, C. & Mills, K. H. Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis. J. Exp. Med 195, 221–31 (2002).

    PubMed  CAS  Google Scholar 

  144. Bendelac, A., Rivera, M. N., Park, S. H. & Roark, J. H. Mouse CDl-specific NK1 T cells: development, specificity, and function. Annu. Rev. Immunol. 15, 535–62 (1997).

    PubMed  CAS  Google Scholar 

  145. Kawano, T. et al. CD1d-restricted and TCR-mediated activation of valphal4 NKT cells by glycosylceramides. Science 278, 1626–9 (1997).

    PubMed  CAS  Google Scholar 

  146. Brossay, L. et al. CDld-mediated recognition of an alpha-galactosylceramide by natural killer T cells is highly conserved through mammalian evolution. J. Exp. Med 188, 1521–8 (1998).

    PubMed  CAS  Google Scholar 

  147. Naidenko, O. V. et al. Binding and antigen presentation of ceramide-containing glycolipids by soluble mouse and human CDld molecules. J. Exp. Med 190, 1069–80 (1999).

    PubMed  CAS  Google Scholar 

  148. Roark, J. H. et al. CD1.1 expression by mouse antigen-presenting cells and marginal zone B cells. J. Immunol. 160, 3121–7 (1998).

    PubMed  CAS  Google Scholar 

  149. Pulendran, B. et al. Developmental pathways of dendritic cells in vivo: distinct function, phenotype, and localization of dendritic cell subsets in FLT3 ligand-treated mice. J. Immunol. 159, 2222–31 (1997).

    PubMed  CAS  Google Scholar 

  150. Koseki, H., Imai, K., Ichikawa, T., Hayata, I. & Taniguchi, M. Predominant use of a particular alpha-chain in suppressor T cell hybridomas specific for keyhole limpet hemocyanin. Int. Immunol. 1, 557–64 (1989).

    PubMed  CAS  Google Scholar 

  151. Porcelli, S., Yockey, C. E., Brenner, M. B. & Balk, S. P. Analysis of T cell antigen receptor (TCR) expression by human peripheral blood CD4-8-alpha/beta T cells demonstrates preferential use of several V beta genes and an invariant TCR alpha chain. J. Exp. Med 178, 1–16 (1993).

    PubMed  CAS  Google Scholar 

  152. Baxter, A. G., Kinder, S. J., Hammond, K. J., Scollay, R. & Godfrey, D. I. Association between alphabetaTCR+CD4-CD8-T-cell deficiency and IDDM in NOD/Lt mice. Diabetes 46, 572–82 (1997).

    PubMed  CAS  Google Scholar 

  153. Iwakoshi, N. N., Greiner, D. L., Rossini, A. A. & Mordes, J. P. Diabetes prone BB rats are severely deficient in natural killer T cells. Autoimmunity 31, 1–14 (1999).

    PubMed  CAS  Google Scholar 

  154. Yoshimoto, T., Bendelac, A., Hu-Li, J. & Paul, W. E. Defective IgE production by SJL mice is linked to the absence of CD4+, NK1.1+ T cells that promptly produce interleukin 4. Proc. Natl. Acad. Sci. USA 92, 11931–4 (1995).

    PubMed  CAS  Google Scholar 

  155. Illes, Z. et al. Differential expression of NK T cell V alpha 24J alpha Q invariant TCR chain in the lesions of multiple sclerosis and chronic inflammatory demyelinating polyneuropathy. J. Immunol. 164, 4375–81 (2000).

    PubMed  CAS  Google Scholar 

  156. Singh, A. K. et al. Natural killer T cell activation protects mice against experimental autoimmune encephalomyelitis. J. Exp. Med 194, 1801–11 (2001).

    PubMed  CAS  Google Scholar 

  157. Jahng, A. W. et al. Activation of natural killer T cells potentiates or prevents experimental autoimmune encephalomyelitis. J. Exp. Med 194, 1789–99 (2001).

    PubMed  CAS  Google Scholar 

  158. Koh, D. R. et al. Less mortality but more relapses in experimental allergic encephalomyelitis in CD8-/-mice. Science 256, 1210–3 (1992).

    PubMed  CAS  Google Scholar 

  159. Jiang, H., Zhang, S. I. & Pernis, B. Role of CD8+ T cells in murine experimental allergic encephalomyelitis. Science 256, 1213–5 (1992).

    PubMed  CAS  Google Scholar 

  160. Miller, A., Lider, O., Roberts, A. B., Sporn, M. B. & Weiner, H. L. Suppressor T cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factor beta after antigen-specific triggering. Proc. Natl. Acad. Sci. USA 89, 421–5 (1992).

    PubMed  CAS  Google Scholar 

  161. Ben-Nun, A., Wekerle, H. & Cohen, I. R. Vaccination against autoimmune encephalomyelitis with T-lymphocyte line cells reactive against myelin basic protein. Nature 292, 60–1 (1981).

    PubMed  CAS  Google Scholar 

  162. Zhang, J. & Raus, J. T-cell vaccination in autoimmune diseases. From laboratory to clinic. Hum. Immunol. 38, 87–96 (1993).

    PubMed  CAS  Google Scholar 

  163. Vandenbark, A. A., Hashim, G. & Offner, H. Immunization with a synthetic T-cell receptor V-region peptide protects against experimental autoimmune encephalomyelitis. Nature 341, 541–4 (1989).

    PubMed  CAS  Google Scholar 

  164. Howell, M. D. et al. Vaccination against experimental allergic encephalomyelitis with T cell receptor peptides. Science 246, 668–70 (1989).

    PubMed  CAS  Google Scholar 

  165. Acha-Orbea, H. et al. Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell 54, 263–73 (1988).

    PubMed  CAS  Google Scholar 

  166. Kumar, V. & Sercarz, E. An integrative model of regulation centered on recognition of TCR peptide/MHC complexes. Immunol. Rev. 182, 113–21 (2001).

    PubMed  CAS  Google Scholar 

  167. Kumar, V., Tabibiazar, R., Geysen, H. M. & Sercarz, E. Immunodominant framework region 3 peptide from TCR V beta 8.2 chain controls murine experimental autoimmune encephalomyelitis. J. Immunol. 154, 1941–50 (1995).

    PubMed  CAS  Google Scholar 

  168. Vainiene, M. et al. Neonatal injection of Lewis rats with recombinant V beta 8.2 induces T cell but not B cell tolerance and increased severity of experimental autoimmune encephalomyelitis. J. Neurosci. Res. 45, 475–86 (1996).

    PubMed  CAS  Google Scholar 

  169. Jiang, H., Braunstein, N. S., Yu, B., Winchester, R. & Chess, L. CD8+ T cells control the TH phenotype of MBP-reactive CD4+ T cells in EAE mice. Proc. Natl. Acad. Sci. USA 98, 6301–6 (2001).

    PubMed  CAS  Google Scholar 

  170. Litzenburger, T. et al. B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice. J. Exp. Med 188, 169–80 (1998).

    PubMed  CAS  Google Scholar 

  171. Myers, K. J., Sprent, J., Dougherty, J. P. & Ron, Y. Synergy between encephalitogenic T cells and myelin basic protein-specific antibodies in the induction of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 41, 1–8 (1992).

    PubMed  CAS  Google Scholar 

  172. Hjelmstrom, P., Juedes, A. E., Fjell, J. & Ruddle, N. H. B-cell-deficient mice develop experimental allergic encephalomyelitis with demyelination after myelin oligodendrocyte glycoprotein sensitization. J. Immunol. 161, 4480–3 (1998).

    PubMed  CAS  Google Scholar 

  173. Lyons, J. A., San, M., Happ, M. P. & Cross, A. H. B cells are critical to induction of experimental allergic encephalomyelitis by protein but not by a short encephalitogenic peptide. Eur. J. Immunol. 29, 3432–9 (1999).

    PubMed  CAS  Google Scholar 

  174. Lyons, J. A., Ramsbottom, M. J. & Cross, A. H. Critical role of antigen-specific antibody in experimental autoimmune encephalomyelitis induced by recombinant myelin oligodendrocyte glycoprotein. Eur. J. Immunol. 32, 1905–13 (2002).

    PubMed  CAS  Google Scholar 

  175. Fillatreau, S., Sweenie, C. H., McGeachy, M. J., Gray, D. & Anderton, S. M. B cells regulate autoimmunity by provision of IL-10. Nature Immunol. 3, 944–50 (2002).

    CAS  Google Scholar 

  176. Pham-Dinh, D. et al. Myelin/oligodendrocyte glycoprotein is a member of a subset of the immunoglobulin superfamily encoded within the major histocompatibility complex. Proc. Natl. Acad. Sci. USA 90, 7990–4 (1993).

    PubMed  CAS  Google Scholar 

  177. Wolf, S. D., Dittel, B. N., Hardardottir, F. & Janeway, C. A., Jr. Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J. Exp. Med 184, 2271–8 (1996).

    PubMed  CAS  Google Scholar 

  178. Mizoguchi, A., Mizoguchi, E., Takedatsu, H., Blumberg, R. S. & Bhan, A. K. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity 16, 219–30 (2002).

    PubMed  CAS  Google Scholar 

  179. Sebzda, E. et al. Selection of the T cell repertoire. Annu. Rev. Immunol. 17, 829–74 (1999).

    PubMed  CAS  Google Scholar 

  180. Goldrath, A. W. & Bevan, M. J. Selecting and maintaining a diverse T-cell repertoire. Nature 402, 255–62 (1999).

    PubMed  CAS  Google Scholar 

  181. Anderton, S. M., Wraith, D.C. Selection and Fine Tuning of the Autoreactive T cell repertoire. Nat. Rev. Immunol. 2, 487–498 (2002).

    PubMed  CAS  Google Scholar 

  182. Heath, V. L., Moore, N. C., Parnell, S. M. & Mason, D. W. Intrathymic expression of genes involved in organ specific autoimmune disease. J. Autoimmun. 11, 309–18 (1998).

    PubMed  CAS  Google Scholar 

  183. Fritz, R. B. & Zhao, M. L. Thymic expression of myelin basic protein (MBP). Activation of MBP-specific T cells by thymic cells in the absence of exogenous MBP. J. Immunol. 157, 5249–53 (1996).

    PubMed  CAS  Google Scholar 

  184. Anderson, A. C. et al. High frequency of autoreactive myelin proteolipid protein-specific T cells in the periphery of naive mice: mechanisms of selection of the self-reactive repertoire. J. Exp. Med 191, 761–70 (2000).

    PubMed  CAS  Google Scholar 

  185. Nave, K. A., Lai, C., Bloom, F. E. & Milner, R. J. Splice site selection in the proteolipid protein (PLP) gene transcript and primary structure of the DM-20 protein of central nervous system myelin. Proc. Natl. Acad. Sci. USA 84, 5665–9 (1987).

    PubMed  CAS  Google Scholar 

  186. Klein, L., Klugmann, M., Nave, K. A., Tuohy, V. K. & Kyewski, B. Shaping the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nature Med. 6, 56–61 (2000).

    PubMed  CAS  Google Scholar 

  187. Fugger, L., Liang, J., Gautam, A., Rothbard, J. B. & McDevitt, H. O. Quantitative analysis of peptides from myelin basic protein binding to the MHC class II protein, I-Au, which confers susceptibility to experimental allergic encephalomyelitis. Mol. Med. 2, 181–8 (1996).

    PubMed  CAS  Google Scholar 

  188. Fairchild, P. J., Wildgoose, R., Atherton, E., Webb, S. & Wraith, D. C. An autoantigenic T cell epitope forms unstable complexes with class II MHC: a novel route for escape from tolerance induction. Int. Immunol. 5, 1151–8 (1993).

    PubMed  CAS  Google Scholar 

  189. Fairchild, P. J., Thorpe, C. J., Travers, P. J. & Wraith, D. C. Modulation of the immune response with T-cell epitopes: the ultimate goal for specific immunotherapy of autoimmune disease. Immunol. 81, 487–96 (1994).

    CAS  Google Scholar 

  190. Pearson, C. I., Gautam, A. M., Rulifson, I. C., Liblau, R. S. & McDevitt, H. O. A small number of residues in the class II molecule I-Au confer the ability to bind the myelin basic protein peptide Acl-11. Proc. Natl. Acad. Sci. USA 96, 197–202 (1999).

    PubMed  CAS  Google Scholar 

  191. Lee, C. et al. Evidence that the autoimmune antigen myelin basic protein (MBP) Acl-9 binds towards one end of the major histocompatibility complex (MHC) cleft. J. Exp. Med 187, 1505–16 (1998).

    PubMed  CAS  Google Scholar 

  192. Wraith, D. C., Smilek, D. E., Mitchell, D. J., Steinman, L. & McDevitt, H. O. Antigen recognition in autoimmune encephalomyelitis and the potential for peptide-mediated immunotherapy. Cell 59, 247–55 (1989).

    PubMed  CAS  Google Scholar 

  193. Ashtonrickardt, P. G. & Tonegawa, S. A Differential-Avidity Model for T-Cell Selection. Immunol. Today 15, 362–366 (1994).

    CAS  Google Scholar 

  194. Sebzda, E. et al. Positive and negative thymocyte selection induced by different concentrations of a single peptide. Science 263, 1615–8 (1994).

    PubMed  CAS  Google Scholar 

  195. Ridgway, W. M., Ito, H., Fasso, M., Yu, C. & Fathman, C. G. Analysis of the role of variation of major histocompatibility complex class II expression on nonobese diabetic (NOD) peripheral T cell response. J. Exp. Med 188, 2267–75 (1998).

    PubMed  CAS  Google Scholar 

  196. Anderton, S. M., Viner, N. J., Matharu, P., Lowrey, P. A. & Wraith, D. C. Influence of a dominant cryptic epitope on autoimmune T cell tolerance. Nature Immunol. 3, 175–181 (2002).

    CAS  Google Scholar 

  197. Manoury, B. et al. An asparaginyl endopeptidase processes a microbial antigen for class II MHC presentation. Nature 396, 695–9 (1998).

    PubMed  CAS  Google Scholar 

  198. Manoury, B. et al. Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP. Nature Immunol. 3, 169–174 (2002).

    CAS  Google Scholar 

  199. Mason, D. A very high level of crossreactivity is an essential feature of the T-cell receptor. Immunol. Today 19, 395–404 (1998).

    PubMed  CAS  Google Scholar 

  200. Borghans, J. A., Noest, A. J. & De Boer, R. J. How specific should immunological memory be? J. Immunol. 163, 569–75 (1999).

    PubMed  CAS  Google Scholar 

  201. Kersh, G. J. & Allen, P. M. Structural basis for T cell recognition of altered peptide ligands: A single T cell receptor can productively recognize a large continuum of related ligands. J. Exp. Med 184, 1259–1268 (1996).

    PubMed  CAS  Google Scholar 

  202. Kersh, G. J. & Allen, P. M. Essential flexibility in the T-cell recognition of antigen. Nature 380, 495–498 (1996).

    PubMed  CAS  Google Scholar 

  203. Fujinami, R. S. & Oldstone, M. B. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science 230, 1043–5 (1985).

    PubMed  CAS  Google Scholar 

  204. Oldstone, M. B., Nerenberg, M., Southern, P., Price, J. & Lewicki, H. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell 65, 319–31 (1991).

    PubMed  CAS  Google Scholar 

  205. Ohashi, P. S. et al. Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 65, 305–17 (1991).

    PubMed  CAS  Google Scholar 

  206. Benoist, C. & Mathis, D. Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry? Nature Immunol. 2, 797–801 (2001).

    CAS  Google Scholar 

  207. Panoutsakopoulou, V. & Cantor, H. On the relationship between viral infection and autoimmunity. J. Autoimmun. 16, 341–5 (2001).

    PubMed  CAS  Google Scholar 

  208. Wucherpfennig, K. W. & Strominger, J. L. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80, 695–705 (1995).

    PubMed  CAS  Google Scholar 

  209. Gautam, A. M. et al. Minimum structural requirements for peptide presentation by major histocompatibility complex class II molecules: implications in induction of autoimmunity. Proc. Natl. Acad. Sci. USA 91, 767–71 (1994).

    PubMed  CAS  Google Scholar 

  210. Carrizosa, A. M. et al. Expansion by self antigen is necessary for the induction of experimental autoimmune encephalomyelitis by T cells primed with a cross-reactive environmental antigen. J. Immunol. 161, 3307–14 (1998).

    PubMed  CAS  Google Scholar 

  211. Ufret-Vincenty, R. L. et al. In vivo survival of viral antigen-specific T cells that induce experimental autoimmune encephalomyelitis. J. Exp. Med 188, 1725–38 (1998).

    PubMed  CAS  Google Scholar 

  212. Gautam, A. M., Liblau, R., Chelvanayagam, G., Steinman, L. & Boston, T. A viral peptide with limited homology to a self peptide can induce clinical signs of experimental autoimmune encephalomyelitis. J. Immunol. 161, 60–4 (1998).

    PubMed  CAS  Google Scholar 

  213. Grogan, J. L. et al. Cross-reactivity of myelin basic protein-specific T cells with multiple microbial peptides: experimental autoimmune encephalomyelitis induction in TCR transgenic mice. J. Immunol. 163, 3764–70 (1999).

    PubMed  CAS  Google Scholar 

  214. Ruiz, P. J. et al. Microbial epitopes act as altered peptide ligands to prevent experimental autoimmune encephalomyelitis. J. Exp. Med 189, 1275–84 (1999).

    PubMed  CAS  Google Scholar 

  215. Barnett, L. A., Whitton, J. L., Wang, L. Y. & Fujinami, R. S. Virus encoding an encephalitogenic peptide protects mice from experimental allergic encephalomyelitis. J. Neuroimmunol. 64, 163–73 (1996).

    PubMed  CAS  Google Scholar 

  216. Olson, J. K., Croxford, J. L., Calenoff, M. A., Dal Canto, M. C. & Miller, S. D. A virus-induced molecular mimicry model of multiple sclerosis. J. Clin. Invest. 108, 311–8(2001).

    PubMed  CAS  Google Scholar 

  217. Olson, J. K., Eagar, T. N. & Miller, S. D. Functional activation of myelin-specific T cells by virus-induced molecular mimicry. J. Immunol. 169, 2719–26 (2002).

    PubMed  CAS  Google Scholar 

  218. Savage, P. A. & Davis, M. M. A kinetic window constricts the T cell receptor repertoire in the thymus. Immunity 14, 243–52 (2001).

    PubMed  CAS  Google Scholar 

  219. Lucas, B., Stefanova, I., Yasutomo, K., Dautigny, N. & Germain, R. N. Divergent changes in the sensitivity of maturing T cells to structurally related ligands underlies formation of a useful T cell repertoire. Immunity 10, 367–76 (1999).

    PubMed  CAS  Google Scholar 

  220. Grossman, Z. & Paul, W. E. Autoreactivity, dynamic tuning and selectivity. Curr. Opin. Immunol. 13, 687–698 (2001).

    PubMed  CAS  Google Scholar 

  221. Germain, R. N. & Stefanova, I. The dynamics of T cell receptor signaling: Complex orchestration and the key roles of tempo and cooperation. Annu. Rev. Immunol. 17, 467–522 (1999).

    PubMed  CAS  Google Scholar 

  222. Munder, M. et al. Reduced self-reactivity of an autoreactive T cell after activation with cross-reactive non-self-ligand. J. Exp. Med. 196, 1151–1162 (2002).

    PubMed  CAS  Google Scholar 

  223. Bouneaud, C., Kourilsky, P. & Bousso, P. Impact of negative selection on the T cell repertoire reactive to a self-peptide: a large fraction of T cell clones escapes clonal deletion. Immunity 13, 829–40 (2000).

    PubMed  CAS  Google Scholar 

  224. Tanchot, C., Barber, D. L., Chiodetti, L. & Schwartz, R. H. Adaptive tolerance of CD4(+) T cells in vivo: Multiple thresholds in response to a constant level of antigen presentation. J. Immunol. 167, 2030–2039 (2001).

    PubMed  CAS  Google Scholar 

  225. Valitutti, S., Muller, S., Cella, M., Padovan, E. & Lanzavecchia, A. Serial triggering of many T-cell receptors by a few peptide-MHC complexes. Nature 375, 148–51 (1995).

    PubMed  CAS  Google Scholar 

  226. Harding, C. V. & Unanue, E. R. Quantitation of antigen-presenting cell MHC class II/peptide complexes necessary for T-cell stimulation. Nature 346, 574–6 (1990).

    PubMed  CAS  Google Scholar 

  227. Kimachi, K., Croft, M. & Grey, H. M. The minimal number of antigen-major histocompatibility complex class II complexes required for activation of naive and primed T cells. Ear. J. Immunol. 27, 3310–7 (1997).

    CAS  Google Scholar 

  228. Nicholson, L. B., Anderson, A. C. & Kuchroo, V. K. Tuning T cell activation threshold and effector function with cross-reactive peptide ligands. Int. Immunol. 12, 205–13 (2000).

    PubMed  CAS  Google Scholar 

  229. Murtaza, A., Kuchroo, V. K. & Freeman, G. J. Changes in the strength of co-stimulation through the B7/CD28 pathway alter functional T cell responses to altered peptide ligands. Int. Immunol. 11, 407–16 (1999).

    PubMed  CAS  Google Scholar 

  230. Drakesmith, H., Chain, B. & Beverley, P. How can dendritic cells cause autoimmune disease? Immunol. Today 21, 214–7 (2000).

    PubMed  CAS  Google Scholar 

  231. Manoury, B., Gregory, W. F., Maizels, R. M. & Watts, C. Bm-CPI-2, a cystatin homolog secreted by the filarial parasite Brugia malayi, inhibits class II MHC-restricted antigen processing. Current Biology 11, 447–51 (2001).

    PubMed  CAS  Google Scholar 

  232. Anderton, S. M. Peptide-based immunotherapy of autoimmunity: a path of puzzles, paradoxes and possibilities. Immunol. 104, 367–376 (2001).

    CAS  Google Scholar 

  233. Franco, A. et al. T cell receptor antagonist peptides are highly effective inhibitors of experimental allergic encephalomyelitis, Eur. J. Immunol. 24, 940–6 (1994).

    PubMed  CAS  Google Scholar 

  234. Kuchroo, V. K. et al. A single TCR antagonist peptide inhibits experimental allergic encephalomyelitis mediated by a diverse T cell repertoire. J. Immunol. 153, 3326–36 (1994).

    PubMed  CAS  Google Scholar 

  235. Nicholson, L. B., Greer, J. M., Sobel, R. A., Lees, M. B. & Kuchroo, V. K. An Altered Peptide Ligand Mediates Immune Deviation and Prevents Autoimmune Encephalomyelitis. Immunity 3, 397–405 (1995).

    PubMed  CAS  Google Scholar 

  236. Nicholson, L. B., Murtaza, A., Hafler, B. P., Sette, A. & Kuchroo, V. K. A T cell receptor antagonist peptide induces T cells that mediate bystander suppression and prevent autoimmune encephalomyelitis induced with multiple myelin antigens. Proc. Natl. Acad. Sci. USA 94, 9279–84 (1997).

    PubMed  CAS  Google Scholar 

  237. Brocke, S. et al. Treatment of experimental encephalomyelitis with a peptide analogue of myelin basic protein. Nature 379, 343–6 (1996).

    PubMed  CAS  Google Scholar 

  238. Karin, N., Mitchell, D. J., Brocke, S., Ling, N. & Steinman, L. Reversal of experimental autoimmune encephalomyelitis by a soluble peptide variant of a myelin basic protein epitope: T cell receptor antagonism and reduction of interferon gamma and tumor necrosis factor alpha production. J. Exp. Med 180, 2227–37 (1994).

    PubMed  CAS  Google Scholar 

  239. Critchfield, J. M. et al. T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis. Science 263, 1139–43 (1994).

    PubMed  CAS  Google Scholar 

  240. Lenardo, M. et al. Mature T lymphocyte apoptosis-immune regulation in a dynamic and unpredictable antigenic environment. Annu. Rev. Immunol. 17, 221–53 (1999).

    PubMed  CAS  Google Scholar 

  241. Anderton, S. M. et al. Fine specificity of the myelin-reactive T cell repertoire: implications for TCR antagonism in autoimmunity. J. Immunol. 161, 3357–64 (1998).

    PubMed  CAS  Google Scholar 

  242. Bielekova, B. et al. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nature Med. 6, 1167–75 (2000).

    PubMed  CAS  Google Scholar 

  243. Kappos, L. et al. Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial. The Altered Peptide Ligand in Relapsing MS Study Group. Nature Med. 6, 1176–82 (2000).

    PubMed  CAS  Google Scholar 

  244. Weigle, W. O. Immunological unresponsiveness. Adv. Immunol. 16, 61–122 (1973).

    PubMed  CAS  Google Scholar 

  245. Metzler, B. & Wraith, D. C. Inhibition of experimental autoimmune encephalomyelitis by inhalation but not oral administration of the encephalitogenic peptide: influence of MHC binding affinity. Int. Immunol. 5, 1159–65 (1993).

    PubMed  CAS  Google Scholar 

  246. Liu, G. Y. & Wraith, D. C. Affinity for class II MHC determines the extent to which soluble peptides tolerize autoreactive T cells in naive and primed adult mice—implications for autoimmunity. Int. Immunol. 7, 1255–63 (1995).

    PubMed  CAS  Google Scholar 

  247. Leadbetter, E. A. et al. Experimental autoimmune encephalomyelitis induced with a combination of myelin basic protein and myelin oligodendrocyte glycoprotein is ameliorated by administration of a single myelin basic protein peptide. J. Immunol. 161,504–12(1998).

    PubMed  CAS  Google Scholar 

  248. al-Sabbagh, A., Miller, A., Santos, L. M. & Weiner, H. L. Antigen-driven tissue-specific suppression following oral tolerance: orally administered myelin basic protein suppresses proteolipid protein-induced experimental autoimmune encephalomyelitis in the SJL mouse. Eur. J. Immunol. 24, 2104–9 (1994).

    PubMed  CAS  Google Scholar 

  249. Gonnella, P. A., Waldner, H. P. & Weiner, H. L. B cell-deficient (mu MT) mice have alterations in the cytokine microenvironment of the gut-associated lymphoid tissue (GALT) and a defect in the low dose mechanism of oral tolerance. J. Immunol. 166, 4456–64 (2001).

    PubMed  CAS  Google Scholar 

  250. Thorstenson, K. M. & Khoruts, A. Generation of anergic and potentially immunoregulatory CD25+CD4 T cells in vivo after induction of peripheral tolerance with intravenous or oral antigen. J. Immunol. 167, 188–95 (2001).

    PubMed  CAS  Google Scholar 

  251. Burkhart, C., Liu, G. Y., Anderton, S. M., Metzler, B. & Wraith, D. C. Peptide-induced T cell regulation of experimental autoimmune encephalomyelitis: a role for IL-10. Int. Immunol. 11, 1625–34(1999).

    PubMed  CAS  Google Scholar 

  252. Massey, E. J. et al. Intranasal peptide-induced peripheral tolerance: the role of IL-10 in regulatory T cell function within the context of experimental autoimmune encephalomyelitis. Vet. Immunol. Immunopathol 87, 357–72 (2002).

    PubMed  CAS  Google Scholar 

  253. Chen, Y. H., Kuchroo, V. K., Inobe, J., Hafler, D. A. & Weiner, H. L. Regulatory T-Cell Clones Induced by Oral Tolerance-Suppression of Autoimmune Encephalomyelitis. Science 265, 1237–1240 (1994).

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Cell Animal and Population Biology, Univeristy of Edinburgh, Edinburgh

    Kelli Ryan & Stephen M Anderton

Authors
  1. Kelli Ryan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen M Anderton
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Weill Medical College of Cornell University, New York

    Ehud Lavi

  2. Queen’s Medical Centre, University Hospital, Nottingham, UK

    Cris S. Constantinescu

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Springer Science+Business Media, Inc.

About this chapter

Cite this chapter

Ryan, K., Anderton, S.M. (2005). T Lymphocytes in EAE. In: Lavi, E., Constantinescu, C.S. (eds) Experimental Models of Multiple Sclerosis. Springer, Boston, MA. https://doi.org/10.1007/0-387-25518-4_11

Download citation

Publish with us

Policies and ethics

Search

Navigation