Viral infection triggers central nervous system autoimmunity via activation of CD8+ T cells expressing dual TCRs.
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.
Department of Immunology, University of Washington, Seattle, Washington, USA.
Qingyong
Q
Ji
Antoine
A
Perchellet
Joan M
JM
Goverman
D000818:Animals; D017951:Antigen Presentation; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002490:Central Nervous System / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006649:Histocompatibility Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000276:immunology; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017634:Self Tolerance; D019076:Transgenes / Q000235:genetics; D014615:Vaccinia / Q000276:immunology*; D014616:Vaccinia virus / Q000472:pathogenicity / Q000502:physiology*
D018984:Epitopes, T-Lymphocyte; D006649:Histocompatibility Antigens; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell