Epitope-specific CD8+ T cells play a differential pathogenic role in the development of a viral disease model for multiple sclerosis.
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.
Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois, USA.
Jinjong
J
Myoung
Hyun Seok
HS
Kang
Wanqiu
W
Hou
Liping
L
Meng
Mauro C
MC
Dal Canto
Byung S
BS
Kim
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D006224:Cricetinae; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology*; D051379:Mice; D009103:Multiple Sclerosis / Q000276:immunology* / Q000821:virology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014777:Virus Diseases / Q000276:immunology*; D014779:Virus Replication
D000939:Epitopes