Project 4, RIG-1-like receptor regulation of T cell immunity against flavivirus

项目4的目标是了解黄病毒感染期间先天免疫感知与保护性T细胞免疫反应调节之间的串扰。西尼罗病毒（WNV）和日本脑炎病毒（JEV）是新兴的蚊媒黄病毒，每年在全球范围内引起病毒引起的脑炎流行。目前还没有批准用于人类治疗西尼罗河病毒感染的疫苗或疗法，目前预防乙脑病毒感染的疫苗不能提供终身保护性免疫。对西尼罗河病毒和乙脑病毒的保护是由先天和适应性免疫反应介导的。RlG-1样受体（RLR）是细胞质病原体识别受体，可识别非自身RNA并通过MAVS接头蛋白发出信号，触发针对西尼罗河病毒和乙脑病毒的先天抗病毒免疫。除了它们在先天免疫中的作用外，我们的实验室最近发现，RLR途径的成分对于在感染后期负责清除病毒的保护性适应性免疫反应的编程至关重要。这包括mavs介导的体液和细胞介导的免疫反应（CD8+、CD4+和Treg反应）以及lgp2介导的西尼罗河病毒感染期间T细胞免疫的调节。发现LGP2以细胞固有的方式控制CD8+ T细胞的存活和效应特性。这些发现表明，在黄病毒感染期间，RLRs调节先天免疫和适应性免疫之间的界面。然而，RLR调控T细胞免疫抵抗黄病毒感染和疫苗接种的免疫学机制尚不清楚。项目4研究将(1)确定RLR信号在调节T细胞启动中的作用和功能；(2)明确MAVS和LGP2在调节效应T细胞和记忆T细胞反应中的T细胞内在功能；(3)确定MAVS和LGP2如何调节记忆性T细胞回忆反应。这项工作将揭示免疫记忆的先天免疫调节的新见解，并确定新的治疗靶点和疫苗保护黄病毒感染的策略。

The goal of Project 4 is to understand the crosstalk between innate immune sensing and regulation of protective T cell immune response during flavivirus infection. West Nile virus (WNV) and Japanese encephalitis virus (JEV) are emerging mosquito-borne flaviviruses that globally cause annual epidemics of virus-induced encephalitis. T here is no approved vaccine or therapy for use in humans to treat WNV infection and the current vaccines to prevent JEV infection do not provide life-long protective immunity. Protection against WNV and JEV is mediated by both innate and adaptive immune responses. The RlG-1 like receptors (RLR) are cytosolic pathogen recognition receptors that recognize non-self RNA and signal through the MAVS adaptor protein to trigger innate antiviral immunity against WNV and JEV. In addition to their role in innate immunity, our laboratory recently discovered that components of the RLR pathway are critical for programming protective adaptive immune responses responsible for clearing virus during the later stages of infection. This includes MAVS-mediated regulation of humoral and cell-mediated immune responses (CD8+, CD4+ and Treg responses) as well as LGP2-mediated regulation of T cell immunity during WNV infection. LGP2 was found to function in a cell-intrinsic manner to control CD8+ T cell survival and effector properties. These findings establish that the RLRs regulate the interface between innate and adaptive immunity during flavivirus infection. However, the immunological mechanism underlying RLR regulation of T cell immunity against flavivirus infection and vaccination are not well understood. Project 4 studies will (1) determine the role of RLR signaling and function in regulating T cell priming; (2) define the Tcell intrinsic function of MAVS and LGP2 in regulating effector and memory T cell responses; (3) determine how MAVS and LGP2 function to regulate memory T cell recall responses. This work will reveal novel insights into innate immune regulation of immunological memory and identify new therapeutic targets and strategies for vaccine protection against flavivirus infection.