CD8+ T Cell Response to Gammaherpesvirus Infection Mediates Inflammation and Fibrosis in Interferon Gamma Receptor-Deficient Mice.
CD8+ T Cell Response to Gammaherpesvirus Infection Mediates Inflammation and Fibrosis in Interferon Gamma Receptor-Deficient Mice.
复制标题
DOI：
10.1371/journal.pone.0135719
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Speck SH
中科院分区：
文献类型：
--
作者：
O'Flaherty BM;Matar CG;Wakeman BS;Garcia A;Wilke CA;Courtney CL;Moore BB;Speck SH
特发性肺纤维化（IPF）是一种病因不明的进行性纤维化疾病，是最严重的间质性肺疾病之一。然而，越来越多的人认识到病毒感染在疾病诱导和/或进展中的作用。多器官纤维化的小动物模型涉及干扰素γ受体缺陷（IFNγR-/-）小鼠的鼠γ疱疹病毒（MHV 68）感染，已用于模拟γ疱疹病毒感染与肺纤维化的相关性。值得注意的是，已经鉴定了几种不能诱导纤维化的MHV 68突变体。我们目前的研究旨在更好地确定独特的MHV 68基因M1在肺纤维化发展中的作用。我们先前已经证明，M1基因编码一种分泌蛋白，该蛋白具有超抗原样功能以驱动Vβ4+ CD 8 + T细胞的扩增和活化。在这里，我们发现M1依赖性纤维化与肺部炎症水平升高相关。我们观察到M1依赖性细胞浸润的先天免疫细胞在感染后28天最显着的差异。此外，在没有M1蛋白表达的情况下，我们观察到肺中的CD 8 + T细胞和MHV 68表位特异性CD 8 + T细胞减少，尽管M1缺失型和野生型MHV 68之间的病毒复制水平相等。值得注意的是，将IFNγR-/-回交到Balb/c背景上，先前已显示其表现出弱的MHV 68驱动的Vβ4+ CD 8 + T细胞扩增，消除了MHV 68诱导的纤维化-进一步暗示活化的Vβ4+ CD 8 + T细胞群诱导纤维化。我们进一步研究了CD 8 + T细胞在通过消耗CD 8 + T细胞诱导纤维化中的作用，这保护了小鼠免受纤维化疾病的影响。综上所述，这些发现与IFNγR-/-小鼠中Vβ4+ CD 8 + T细胞作为纤维化疾病介质的假设作用一致。
Idiopathic pulmonary fibrosis (IPF), one of the most severe interstitial lung diseases, is a progressive fibrotic disorder of unknown etiology. However, there is growing appreciation for the role of viral infection in disease induction and/or progression. A small animal model of multi-organ fibrosis, which involves murine gammaherpesvirus (MHV68) infection of interferon gamma receptor deficient (IFNγR-/-) mice, has been utilized to model the association of gammaherpesvirus infections and lung fibrosis. Notably, several MHV68 mutants which fail to induce fibrosis have been identified. Our current study aimed to better define the role of the unique MHV68 gene, M1, in development of pulmonary fibrosis. We have previously shown that the M1 gene encodes a secreted protein which possesses superantigen-like function to drive the expansion and activation of Vβ4+ CD8+ T cells. Here we show that M1-dependent fibrosis is correlated with heightened levels of inflammation in the lung. We observe an M1-dependent cellular infiltrate of innate immune cells with most striking differences at 28 days-post infection. Furthermore, in the absence of M1 protein expression we observed reduced CD8+ T cells and MHV68 epitope specific CD8+ T cells to the lungs—despite equivalent levels of viral replication between M1 null and wild type MHV68. Notably, backcrossing the IFNγR-/- onto the Balb/c background, which has previously been shown to exhibit weak MHV68-driven Vβ4+ CD8+ T cell expansion, eliminated MHV68-induced fibrosis—further implicating the activated Vβ4+ CD8+ T cell population in the induction of fibrosis. We further addressed the role that CD8+ T cells play in the induction of fibrosis by depleting CD8+ T cells, which protected the mice from fibrotic disease. Taken together these findings are consistent with the hypothesized role of Vβ4+ CD8+ T cells as mediators of fibrotic disease in IFNγR-/- mice.