Viral Infection Triggers Central Nervous System Autoimmunity via Activation of CD8+ T Cells Expressing Dual TCRs

Nat Immunol. 2010 Jul;11(7):628-34. doi: 10.1038/ni.1888. Epub 2010 Jun 6.

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

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigen Presentation
  • Autoimmunity
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / virology
  • Cell Proliferation
  • Cells, Cultured
  • Central Nervous System / immunology*
  • Central Nervous System / pathology
  • Disease Models, Animal
  • Epitopes, T-Lymphocyte / genetics
  • Epitopes, T-Lymphocyte / immunology
  • Epitopes, T-Lymphocyte / metabolism*
  • Histocompatibility Antigens / immunology
  • Histocompatibility Antigens / metabolism
  • Humans
  • Lymphocyte Activation
  • Mice
  • Mice, Transgenic
  • Multiple Sclerosis / immunology
  • Myelin Basic Protein / genetics
  • Myelin Basic Protein / immunology
  • Myelin Basic Protein / metabolism*
  • Peptide Fragments / genetics
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism*
  • Self Tolerance
  • Transgenes / genetics
  • Vaccinia / immunology*
  • Vaccinia virus / pathogenicity
  • Vaccinia virus / physiology*

Substances

  • Epitopes, T-Lymphocyte
  • Histocompatibility Antigens
  • Myelin Basic Protein
  • Peptide Fragments
  • Receptors, Antigen, T-Cell