Division of Biological Sciences, Molecular Biology Section, University of California, San Diego, La Jolla, CA 92093; and.
Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093.
J Immunol. 2018 Feb 15;200(4):1335-1346. doi: 10.4049/jimmunol.1601870. Epub 2018 Jan 8.
Caspase-8 (CASP8) is known as an executioner of apoptosis, but more recent studies have shown that it participates in the regulation of necroptosis and innate immunity. In this study, we show that CASP8 negatively regulates retinoic acid-inducible gene I (RIG-I) signaling such that, in its absence, stimulation of the RIG-I pathway in dendritic cells (DCs) produced modestly enhanced activation of IFN regulatory factor 3 with correspondingly greater amounts of proinflammatory cytokines. In addition, mice lacking DC-specific CASP8 ( mice) develop age-dependent symptoms of autoimmune disease characterized by hyperactive DCs and T cells, spleen and liver immunopathology, and the appearance of Th1-polarized CD4 T cells. Such mice infected with chronic lymphocytic choriomeningitis virus, an RNA virus detected by RIG-I, mounted an enhanced lymphocytic choriomeningitis virus-specific immune response as measured by increased proportions of Ag-specific CD4 T cells and multicytokine-producing CD4 and CD8 T cells. These results show that CASP8 subtly modulates DC maturation, which controls the spontaneous appearance of autoimmune T cells while simultaneously attenuating the acquired immune system and its potential to control a persistent viral infection.
半胱氨酸天冬氨酸蛋白酶 8（CASP8）被认为是细胞凋亡的执行者，但最近的研究表明，它参与了坏死性凋亡和先天免疫的调节。在本研究中，我们表明 CASP8 负调控视黄酸诱导基因 I（RIG-I）信号通路，以致在树突状细胞（DC）中缺乏 CASP8 时，RIG-I 通路的刺激会适度增强干扰素调节因子 3 的激活，同时产生更多的促炎细胞因子。此外，缺乏 DC 特异性 CASP8（ CASP8 -/- ）的小鼠表现出年龄依赖性自身免疫疾病的症状，其特征是 DC 和 T 细胞过度活跃、脾脏和肝脏免疫病理学以及 Th1 极化的 CD4 T 细胞出现。这些感染慢性淋巴细胞脉络丛脑膜炎病毒（一种被 RIG-I 检测到的 RNA 病毒）的小鼠表现出增强的淋巴细胞脉络丛脑膜炎病毒特异性免疫反应，表现为 Ag 特异性 CD4 T 细胞和多细胞因子产生的 CD4 和 CD8 T 细胞比例增加。这些结果表明，CASP8 微妙地调节 DC 的成熟，从而控制自发性自身反应性 T 细胞的出现，同时减弱获得性免疫系统及其控制持续性病毒感染的潜力。
