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

项目摘要。先天适应性免疫界面代表了免疫系统的组成部分的作用部位。 先天性免疫和适应性免疫都相互交叉参与，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界面的作用被认为是必不可少的， 建立针对病毒感染的保护性免疫和免疫记忆。III型干扰素（IFN-λ）是一种 一种在先天-适应性免疫界面起作用并对介导先天免疫至关重要的细胞因子 保护粘膜屏障。IFN-λ提供针对甲型流感病毒（IAV）感染的治疗益处， 然而，没有定义它如何在固有自适应接口内操作。我们利用了一种小鼠模型， IAV感染，研究IFN-λ在先天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，Ifnlr 1-/-小鼠具有钝化的效应CD 8 + T细胞应答 与WT小鼠相比，在异亚型IAV再攻击时表现出降低的存活率。枝晶分析 细胞（DC）的研究表明，IFN-λ信号传导指导CD 103 + DC迁移和功能，以开发最佳的抗病毒药物， CD 8 + T细胞应答。此外，初步的生物信息学分析表明，IFN-λ对于控制 IAV感染过程中DC中的IL 10免疫调节网络我们的观察表明IFN-λ与先天性 和获得性免疫以指导DC编程针对IAV的有效T细胞免疫。我们假设IFN-λ DC中的信号传导调节IL-10程序，该程序对于有效T细胞记忆的发展至关重要， 免疫IAV。因此，本提案中的研究旨在：1）确定IFN-λ对 记忆性CD 4+和CD 8 + T细胞应答的产生和2）阐明IFN-λ对IL-10的调节， 编程DC功能。这些研究的结果将确定IFN-λ在先天适应性 在编程针对IAV感染有效免疫中的免疫界面和基于IFN-λ的疫苗， 免疫治疗策略，以防止和限制感染。 !

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. !