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

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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. !