Epitope-specific CD8+ T cells play a differential pathogenic role in the development of a viral disease model for multiple sclerosis

Jinjong Myoung, Hyun Seok Kang, Wanqiu Hou, Liping Meng, Mauro C. Dal Canto, Byung S. Kim*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Theiler's virus-induced demyelinating disease has been extensively investigated as a model for persistent viral infection and multiple sclerosis (MS). However, the role of CD8+ T cells in the development of disease remains unclear. To assess the role of virusspecific CD8+ T cells in the pathogenesis of demyelinating disease, a single amino acid substitution was introduced into the predominant viral epitope (VP3 from residues 159 to 166 [VP3159-166]) and/or a subdominant viral epitope (VP3173-181) of susceptible SJL/J mice by site-directed mutagenesis. The resulting variant viruses (N160V, P179A, and N160V/P179A) failed to induce CD8+ T cell responses to the respective epitopes. Surprisingly, mice infected with N160V or N160V/P179A virus, which lacks CD8+ T cells against VP3159-166, did not develop demyelinating disease, in contrast to wild-type virus or P179A virus lacking VP3173-181-specific CD8+ T cells. Our findings clearly show that the presence of VP3159-166-specific CD8+ T cells, rather than viral persistence itself, is strongly correlated with disease development. VP3173-181-specific CD8+ T cells in the central nervous system (CNS) of these virus-infected mice expressed higher levels of transforming growth factor β, forkhead box P3, interleukin- 22 (IL-22), and IL-17 mRNA but caused minimal cytotoxicity compared to that caused by VP3159-166-specific CD8+ T cells. VP3159-166-specific CD8+ T cells exhibited high functional avidity for gamma interferon production, whereas VP3173-181-specific CD8+ T cells showed low avidity. To our knowledge, this is the first report indicating that the induction of the IL-17-producing CD8+ T cell type is largely epitope specific and that this specificity apparently plays a differential role in the pathogenicity of virus- induced demyelinating disease. These results strongly advocate for the careful consideration of CD8+ T cell-mediated intervention of virus-induced inflammatory diseases.

Original languageEnglish (US)
Pages (from-to)13717-13728
Number of pages12
JournalJournal of virology
Volume86
Issue number24
DOIs
StatePublished - Dec 2012

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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