Abstract
Multiple sclerosis is an inflammatory, demyelinating, central nervous system disease mediated by myelin-specific T cells. Environmental triggers that cause the breakdown of myelin-specific T cell tolerance are unknown. Here we found that CD8(+) myelin basic protein (MBP)-specific T cell tolerance was broken and autoimmunity was induced by infection with a virus that did not express MBP cross-reactive epitopes and did not depend on bystander activation. Instead, the virus activated T cells expressing dual T cell antigen receptors (TCRs) that were able to recognize both MBP and viral antigens. Our results demonstrate the importance of dual TCR-expressing T cells in autoimmunity and suggest a mechanism by which a ubiquitous viral infection could trigger autoimmunity in a subset of infected people, as suggested by the etiology of multiple sclerosis.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antigen Presentation
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Autoimmunity
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism*
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CD8-Positive T-Lymphocytes / pathology
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CD8-Positive T-Lymphocytes / virology
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Cell Proliferation
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Cells, Cultured
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Central Nervous System / immunology*
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Central Nervous System / pathology
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Disease Models, Animal
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Epitopes, T-Lymphocyte / genetics
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Epitopes, T-Lymphocyte / immunology
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Epitopes, T-Lymphocyte / metabolism*
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Histocompatibility Antigens / immunology
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Histocompatibility Antigens / metabolism
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Humans
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Lymphocyte Activation
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Mice
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Mice, Transgenic
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Multiple Sclerosis / immunology
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Myelin Basic Protein / genetics
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Myelin Basic Protein / immunology
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Myelin Basic Protein / metabolism*
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Peptide Fragments / genetics
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / metabolism*
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Self Tolerance
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Transgenes / genetics
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Vaccinia / immunology*
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Vaccinia virus / pathogenicity
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Vaccinia virus / physiology*
Substances
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Epitopes, T-Lymphocyte
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Histocompatibility Antigens
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Myelin Basic Protein
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Peptide Fragments
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Receptors, Antigen, T-Cell