Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois, USA.
J Virol. 2012 Dec;86(24):13717-28. doi: 10.1128/JVI.01733-12. Epub 2012 Oct 10.
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.
Theiler 病毒诱导的脱髓鞘疾病已被广泛研究作为持续性病毒感染和多发性硬化症 (MS) 的模型。然而，CD8(+) T 细胞在疾病发展中的作用仍不清楚。为了评估病毒特异性 CD8(+) T 细胞在脱髓鞘疾病发病机制中的作用，通过定点诱变技术在易感 SJL/J 小鼠中引入了单一氨基酸取代，该取代位于主要病毒表位（VP3 残基 159 到 166 [VP3(159-166)]）和/或次要病毒表位（VP3(173-181)）。产生的变异病毒（N160V、P179A 和 N160V/P179A）未能诱导针对各自表位的 CD8(+) T 细胞反应。令人惊讶的是，感染 N160V 或 N160V/P179A 病毒的小鼠，这些病毒缺乏针对 VP3(159-166)的 CD8(+) T 细胞，并未发展脱髓鞘疾病，而野生型病毒或缺乏 VP3(173-181)-特异性 CD8(+) T 细胞的 P179A 病毒则发展了脱髓鞘疾病。我们的研究结果清楚地表明，VP3(159-166)-特异性 CD8(+) T 细胞的存在，而不是病毒的持续存在，与疾病的发展密切相关。感染这些病毒的小鼠中枢神经系统 (CNS) 中的 VP3(173-181)-特异性 CD8(+) T 细胞表达更高水平的转化生长因子 β、叉头框 P3、白细胞介素-22 (IL-22) 和 IL-17 mRNA，但与 VP3(159-166)-特异性 CD8(+) T 细胞相比，引起的细胞毒性最小。VP3(159-166)-特异性 CD8(+) T 细胞对产生γ干扰素表现出高功能亲和力，而 VP3(173-181)-特异性 CD8(+) T 细胞表现出低亲和力。据我们所知，这是第一个表明诱导产生 IL-17 的 CD8(+) T 细胞类型在很大程度上是表位特异性的报告，并且这种特异性显然在病毒诱导的脱髓鞘疾病的发病机制中发挥了不同的作用。这些结果强烈主张在病毒诱导的炎症性疾病中仔细考虑 CD8(+) T 细胞介导的干预。
