RIG-I Signaling Is Critical for Efficient Polyfunctional T Cell Responses during Influenza Virus Infection

Retinoic acid inducible gene-I (RIG-I) is an innate RNA sensor that recognizes the influenza A virus (IAV) RNA genome and activates antiviral host responses. Here, we demonstrate that RIG-I signaling plays a crucial role in restricting IAV tropism and regulating host immune responses. Mice deficient in the RIG-I-MAVS pathway show defects in migratory dendritic cell (DC) activation, viral antigen presentation, and priming of CD8+ and CD4+ T cell responses during IAV infection. These defects result in decreased frequency of polyfunctional effector T cells and lowered protection against heterologous IAV challenge. In addition, our data show that RIG-I activation is essential for protecting epithelial cells and hematopoietic cells from IAV infection. These diverse effects of RIG-I signaling are likely imparted by the actions of type I interferon (IFN), as addition of exogenous type I IFN is sufficient to overcome the defects in antigen presentation by RIG-I deficient BMDC. Moreover, the in vivo T cell defects in RIG-I deficient mice can be overcome by the activation of MDA5 –MAVS via poly I:C treatment. Taken together, these findings demonstrate that RIG-I signaling through MAVS is critical for determining the quality of polyfunctional T cell responses against IAV and for providing protection against subsequent infection from heterologous or novel pandemic IAV strains.视黄酸诱导基因I（Retinoic acid inducible gene-I, RIG-I）是一类固有RNA感受器，可识别甲型流感病毒（influenza A virus, IAV）的RNA基因组并激活抗病毒宿主免疫应答。本研究证实，RIG-I信号通路在限制甲型流感病毒嗜性以及调控宿主免疫应答过程中发挥关键作用。RIG-I-MAVS通路缺陷小鼠在甲型流感病毒感染期间，其迁移性树突状细胞（dendritic cell, DC）活化、病毒抗原呈递以及CD8+和CD4+ T细胞应答启动均存在缺陷。此类缺陷会导致多功能效应性T细胞的频率降低，同时降低机体对异源甲型流感病毒攻毒的保护能力。此外，本研究数据显示，RIG-I活化对于上皮细胞与造血细胞抵御甲型流感病毒感染至关重要。RIG-I信号通路的这些多样生物学效应大概率由I型干扰素（type I interferon, IFN）介导，因为外源性添加I型干扰素足以弥补RIG-I缺陷型骨髓来源树突状细胞（BMDC）在抗原呈递方面的功能缺陷。进一步而言，RIG-I缺陷小鼠体内的T细胞功能缺陷可通过聚肌胞苷酸（poly I:C）激活MDA5-MAVS通路得以修复。综上，本研究结果表明，经由MAVS介导的RIG-I信号通路，对于调控抗甲型流感病毒的多功能T细胞应答质量，以及抵御后续异源或新型大流行性甲型流感病毒毒株的感染均具有关键意义。