Epitope-Specific CD8 + T Cells Play a Differential Pathogenic Role in the Development of a Viral Disease Model for Multiple Sclerosis

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 virus-specific 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 [VP3 159-166 ]) and/or a subdominant viral epitope (VP3 173-181 ) 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 VP3 159-166 , did not develop demyelinating disease, in contrast to wild-type virus or P179A virus lacking VP3 173-181 -specific CD8 + T cells. Our findings clearly show that the presence of VP3 159-166 -specific CD8 + T cells, rather than viral persistence itself, is strongly correlated with disease development. VP3 173-181 -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 VP3 159-166 -specific CD8 + T cells. VP3 159-166 -specific CD8 + T cells exhibited high functional avidity for gamma interferon production, whereas VP3 173-181 -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.