Mechanisms of Interferon-Lambda Programming at the Innate-Adaptive Immune Interface for Protection Against Virus Infection

项目摘要。先天适应性免疫接口代表作用部位，其组件 先天免疫和获得性免疫相互交叉，以编程适应性免疫的效应器动作 免疫反应。先天-适应性免疫接口的作用被认为是 建立针对病毒感染的保护性免疫和免疫记忆。III型干扰素(λ)是一种 在先天免疫-适应性免疫界面起作用的细胞因子，对调节先天免疫至关重要 粘膜屏障的保护。干扰素-λ对甲型流感病毒感染有治疗作用， 然而，它如何在先天自适应接口中运行并没有定义。我们已经利用了一种小鼠模型 研究干扰素-λ在机体天然适应性界面免疫调节中的作用 呼吸道病毒感染。我们的研究表明Ifnlr1-/-小鼠的CD8+T细胞反应迟钝 与WT小鼠相比，在异亚型IAV再次攻击时，小鼠的存活率降低。枝晶组织的分析 细胞(DC)发现干扰素-λ信号引导CD103+DC迁移和功能发展最佳的抗病毒作用 CD8+T细胞反应。此外，初步的生物信息学分析表明，干扰素-λ对于控制AN是必不可少的。 IL10在IAV感染过程中树突状细胞的免疫调节网络。我们的观察表明，干扰素-λ桥是先天的 和获得性免疫，以指导DC对IAV进行有效的T细胞免疫。我们假设干扰素-λ DC中的信号调节IL-10程序，IL-10对持续有效的T细胞记忆的发展至关重要 对IAV的豁免权。因此，本方案中的研究旨在：1)确定干扰素-λ对 产生记忆CD_4~+和CD_8~+T细胞应答；2)阐明干扰素-λ对IL-10的调节作用 DC函数编程。这些研究的结果将确定干扰素-λ在先天适应性中的作用 免疫接口在规划有效免疫以对抗禽流感病毒感染和告知干扰素-λ疫苗和 预防和限制感染的免疫治疗策略。 好了！

Project Summary. The innate-adaptive immune interface represents the site of action where components of both innate and adaptive immunity cross-engage each other to program the effector actions of the adaptive immune response. The actions of the innate-adaptive immune interface are considered essential for establishing protective immunity and immune memory against virus infection. Type III interferon (IFN-λ) is a cytokine that functions at the innate-adaptive immune interface and is critical for mediating innate immune protection at mucosal barriers. IFN-λ provides therapeutic benefit against Influenza A virus (IAV) infection, however how it operates within the innate-adaptive interface is not defined. We have utilized a murine model of IAV infection to study the contribution of IFN-λ in regulation of immunity at the innate-adaptive interface during respiratory virus infection. Our studies show Ifnlr1-/- mice have blunted effector CD8+ T cell responses compared to WT mice and exhibit reduced survival upon heterosubtypic IAV re-challenge. Analysis of dendritic cells (DCs) reveals that IFN-λ signaling directs CD103+ DC migration and function to develop optimal anti-viral CD8+ T cell responses. Further, preliminary bioinformatic analysis suggests IFN-λ is essential for control of an Il10 immunoregulatory network in DCs during IAV infection. Our observations reveal that IFN-λ bridges innate and adaptive immunity to direct DCs to program effective T cell immunity against IAV. We hypothesize IFN-λ signaling in DC regulates an IL-10 program critical for development of effective T cell memory for lasting immunity against IAV. Thus, the studies in this proposal aim to: 1) determine the contribution of IFN-λ to generation of memory CD4+ and CD8+ T cell responses and 2) elucidate IFN-λ regulation of IL-10 in programming DC functions. Results from these studies will define the role of IFN-λ at the innate-adaptive immune interface in programming effective immunity against IAV infection and inform IFN-λ-based vaccine and immune therapy strategies to prevent and limit infection. !