Viral infection triggers central nervous system autoimmunity via activation of CD8+ T cells expressing dual TCRs

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Abstract
Whether environmental antigens can elicit autoimmunity remains unclear. Goverman and colleagues show that viral infection breaks self-tolerance via activation of CD8+ T cells expressing dual T cell antigen receptors, without bystander activation or molecular mimicry. 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.