Abstract
Multiple sclerosis (MS) is a severe central nervous system disease. Experimental autoimmune encephalomyelitis (EAE) mimics MS in mice. We report that spontaneous development of EAE in RAG-1-deficient mice transgenic for a myelin basic protein (MBP)-specific TCR (TgMBP+/RAG-1-/-) requires expression of the T cell costimulatory molecule CD28. Surprisingly, T cells from CD28-/-TgMBP+/RAG-1-/- mice proliferate and produce IL-2 in response to MBP1-17 peptide in vitro, excluding clonal anergy as the mechanism of CD28-regulated pathogenesis. Proliferation of autoaggressive T cells was dependent on the concentration of the MBP peptide, as was the development of MBP-induced EAE in CD28-deficient PL/J mice. These results provide the first genetic evidence that CD28 costimulation is crucial for MBP-specific T cell activation in vivo and the initiation of spontaneous EAE.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Autoantigens / administration & dosage
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CD28 Antigens / biosynthesis
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CD28 Antigens / genetics
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CD28 Antigens / physiology*
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Cell Differentiation / immunology
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Cytokines / biosynthesis
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Dose-Response Relationship, Immunologic
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Encephalomyelitis, Autoimmune, Experimental / etiology*
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Lymphocyte Activation / immunology
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Mice
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Mice, Inbred Strains
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Mice, Transgenic
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Molecular Sequence Data
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Myelin Basic Protein / genetics
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Myelin Basic Protein / immunology
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
Substances
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Autoantigens
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CD28 Antigens
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Cytokines
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Myelin Basic Protein