Institute of Immunology, PLA, Third Military Medical University, Chongqing, P. R. China.
PLoS Pathog. 2011 Jul;7(7):e1001347. doi: 10.1371/journal.ppat.1001347. Epub 2011 Jul 7.
The inhibitory receptor programmed death-1 (PD-1) has the capacity to maintain peripheral tolerance and limit immunopathological damage; however, its precise role in fulminant viral hepatitis (FH) has yet to be described. Here, we investigated the functional mechanisms of PD-1 as related to FH pathogenesis induced by the murine hepatitis virus strain-3 (MHV-3). High levels of PD-1-positive CD4(+), CD8(+) T cells, NK cells and macrophages were observed in liver, spleen, lymph node and thymus tissues following MHV-3 infection. PD-1-deficient mice exhibited significantly higher expression of the effector molecule which initiates fibrinogen deposition, fibrinogen-like protein 2 (FGL2), than did their wild-type (WT) littermates. As a result, more severe tissue damage was produced and mortality rates were higher. Fluorescence double-staining revealed that FGL2 and PD-1 were not co-expressed on the same cells, while quantitative RT-PCR demonstrated that higher levels of IFN-γ and TNF-α mRNA transcription occurred in PD-1-deficient mice in response to MHV-3 infection. Conversely, in vivo blockade of IFN-γ and TNF-α led to efficient inhibition of FGL2 expression, greatly attenuated the development of tissue lesions, and ultimately reduced mortality. Thus, the up-regulation of FGL2 in PD-1-deficient mice was determined to be mediated by IFN-γ and TNF-α. Taken together, our results suggest that PD-1 signaling plays an essential role in decreasing the immunopathological damage induced by MHV-3 and that manipulation of this signal might be a useful strategy for FH immunotherapy.
抑制性受体程序性死亡受体-1（PD-1）具有维持外周耐受和限制免疫病理损伤的能力；然而，其在暴发性病毒性肝炎（FH）中的确切作用尚未描述。在这里，我们研究了 PD-1 在由鼠肝炎病毒株 3（MHV-3）引起的 FH 发病机制中的功能机制。在 MHV-3 感染后，在肝、脾、淋巴结和胸腺组织中观察到高水平的 PD-1 阳性 CD4(+)、CD8(+)T 细胞、NK 细胞和巨噬细胞。与野生型（WT）同窝仔相比，PD-1 缺陷型小鼠表现出明显更高的起始纤维蛋白原沉积的效应分子纤维蛋白原样蛋白 2（FGL2）的表达。结果，产生了更严重的组织损伤，死亡率更高。荧光双重染色显示 FGL2 和 PD-1 不在同一细胞上共表达，而定量 RT-PCR 表明 PD-1 缺陷型小鼠在感染 MHV-3 后，IFN-γ 和 TNF-αmRNA 转录水平更高。相反，体内阻断 IFN-γ 和 TNF-α 可有效抑制 FGL2 的表达，极大地减轻组织损伤的发展，最终降低死亡率。因此，PD-1 缺陷型小鼠中 FGL2 的上调被确定由 IFN-γ 和 TNF-α介导。总之，我们的结果表明 PD-1 信号在降低 MHV-3 诱导的免疫病理损伤中起着重要作用，并且对该信号的操纵可能是 FH 免疫治疗的一种有用策略。
