Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois, USA.
J Virol. 2013 Nov;87(21):11538-51. doi: 10.1128/JVI.01967-13. Epub 2013 Aug 21.
Infection with Theiler's murine encephalomyelitis virus (TMEV) in the central nervous system (CNS) of susceptible mice results in an immune-mediated demyelinating disease which is considered a relevant viral model of human multiple sclerosis. We previously demonstrated that the expression of positive costimulatory molecules (CD40, CD80, and CD86) is higher on the microglia of TMEV-resistant C57BL/6 (B6) mice than the microglia of TMEV-susceptible SJL/J (SJL) mice. In this study, we analyzed the expression levels of the negative costimulatory molecules PD-1 and PDL-1 in the CNS of TMEV-infected SJL mice and B6 mice. Our results indicated that TMEV infection induces the expression of both PD-1 and PDL-1 on microglia and macrophages in the CNS but not in the periphery. The expression of PD-1 only on CNS-infiltrating macrophages and not on resident microglia was considerably higher (>4-fold) in TMEV-infected SJL mice than TMEV-infected B6 mice. We further demonstrated that interleukn-6 (IL-6) is necessary to induce the maximal expression of PDL-1 but not PD-1 after TMEV infection using IL-6-deficient mice and IL-6-transgenic mice in conjunction with recombinant IL-6. In addition, cells from type I interferon (IFN) receptor knockout mice failed to upregulate PD-1 and PDL-1 expression after TMEV infection in vitro, indicating that type I IFN signaling is associated with the upregulation. However, other IFN signaling may also participate in the upregulation. Taken together, these results strongly suggest that the expression of PD-1 and PDL-1 in the CNS is primarily upregulated following TMEV infection via type I IFN signaling and the maximal expression of PDL-1 additionally requires IL-6 signaling.
感染 Theiler's 鼠脑脊髓炎病毒（TMEV）会导致易感小鼠中枢神经系统（CNS）发生免疫介导的脱髓鞘疾病，这被认为是人类多发性硬化症的一种相关病毒模型。我们之前的研究表明，TMEV 抗性 C57BL/6（B6）小鼠的小胶质细胞上表达的正共刺激分子（CD40、CD80 和 CD86）比 TMEV 易感 SJL/J（SJL）小鼠的小胶质细胞上更高。在这项研究中，我们分析了 TMEV 感染的 SJL 小鼠和 B6 小鼠中枢神经系统中负共刺激分子 PD-1 和 PDL-1 的表达水平。结果表明，TMEV 感染诱导 CNS 中小胶质细胞和巨噬细胞表达 PD-1 和 PDL-1，但在外周组织中不表达。在 TMEV 感染的 SJL 小鼠中，PD-1 仅在 CNS 浸润的巨噬细胞上表达，而不在常驻小胶质细胞上表达，其表达水平明显高于 TMEV 感染的 B6 小鼠（>4 倍）。我们进一步证明，白细胞介素 6（IL-6）是诱导 TMEV 感染后 PDL-1 最大表达所必需的，但不是 PD-1 的表达，方法是使用 IL-6 缺陷小鼠和 IL-6 转基因小鼠结合重组 IL-6。此外，I 型干扰素（IFN）受体敲除小鼠的细胞在体外感染 TMEV 后未能上调 PD-1 和 PDL-1 的表达，表明 I 型 IFN 信号与上调有关。然而，其他 IFN 信号也可能参与上调。总之，这些结果强烈表明，PD-1 和 PDL-1 在中枢神经系统中的表达主要是通过 I 型 IFN 信号上调的，而 PDL-1 的最大表达还需要 IL-6 信号。
