Type III interferon (IFN-λ) is important for innate immune protection at mucosal surfaces and has therapeutic benefit against influenza A virus (IAV) infection. However, the mechanisms by which IFN-λ programs adaptive immune protection against IAV are undefined. Here we found that IFN-λ signaling in dendritic cell (DC) populations was critical for the development of protective IAV-specific CD8+ T cell responses. Mice lacking the IFN-λ receptor (Ifnlr1−/−) had blunted CD8+ T cell responses relative to wild type and exhibited reduced survival after heterosubtypic IAV re-challenge. Analysis of DCs revealed IFN-λ signaling directed the migration and function of CD103+ DCs for development of optimal antiviral CD8+ T cell responses, and bioinformatic analyses identified IFN-λ regulation of a DC IL-10 immunoregulatory network. Thus, IFN-λ serves a critical role in bridging innate and adaptive immunity from lung mucosa to lymph nodes to program DCs to direct effective T cell immunity against IAV.
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We would like to thank the Cell Analysis Facility Flow Cytometry and Imaging Core in the Department of Immunology at the University of Washington and E. Smith for technical assistance. We would like to thank A.M. Kell and M.E. Long for their critical reading of this manuscript. E.A.H. is supported by American Heart Association award 17POST33660907. This work was also supported by National Institutes of Health grants T32AI007509 (E.A.H.), AI132962 (R.A.L.), AI108765 (R.S.), AI104002 (M.G.), AI118916 (M.G.), AI083019 (M.G.) and AI127463 (M.G.).