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

Nature Immunology volume 11, pages 628–634 (2010)Cite this article

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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.

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Figure 1: Infection with wild-type vaccinia virus induces autoimmune disease in 8.8 mice.
Figure 2: Wild-type vaccinia virus does not stimulate 8.8 T cells via bystander activation.
Figure 3: The 8.8 TCR is not cross-reactive to wild-type vaccinia virus epitopes.
Figure 4: Activation of Rag2+/+ 8.8 T cells by wild-type vaccinia virus requires expression of endogenous TCR chains.
Figure 5: Infection of 8.8 mice with wild-type vaccinia virus 'preferentially' expands CD8+ Vβ6+Vβ8+ T cell populations that respond to vaccinia virus epitopes.
Figure 6: Vac-MBP activates Rag2−/− 8.8 T cells to induce autoimmunity but wild-type vaccinia virus does not.

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Acknowledgements

We thank N. Mausolf for animal husbandry and technical assistance and S. Lee and E. Pierson for critical comments on the manuscript. Supported by the National Institutes of Health (AI07272737 to J.M.G.).

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  1. Antoine Perchellet

    Present address: Present address: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, USA.,

Authors and Affiliations

  1. Department of Immunology, University of Washington, Seattle, Washington, USA

    Qingyong Ji, Antoine Perchellet & Joan M Goverman

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  1. Qingyong Ji
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  2. Antoine Perchellet
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Contributions

Q.J. did most of the experiments and analyzed the data; A.P. did the initial disease-induction experiments and critiqued the manuscript; Q.J. and J.M.G. designed the study and wrote the manuscript; and J.M.G. secured the funding.

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Correspondence to Joan M Goverman.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 and Table 1 (PDF 3398 kb)

Supplementary Video 1

EAE in 8.8 mice after wild-type vaccinia infection. Female 8.8 mice were intraperitoneally infected with 5×106 pfu of wild-type vaccinia virus. This video was taken one month after vaccinia infection. (MOV 2886 kb)

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Ji, Q., Perchellet, A. & Goverman, J. Viral infection triggers central nervous system autoimmunity via activation of CD8+ T cells expressing dual TCRs. Nat Immunol 11, 628–634 (2010). https://doi.org/10.1038/ni.1888

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