IFN-lambda orchestrates an IL-10 immunoregulatory program in dendritic cells critical for T cell-mediated protection against influenza virus infection

Abstract

Abstract Influenza virus (IAV) infection remains a major global health burden that requires development therapeutic and vaccination strategies to limit infection and drive robust and durable protective immune responses. Type III interferon (IFN), IFN-lambda, restricts IAV infection in vivo compared to type I IFN. However, the contribution of IFN-lambda to generating adaptive immune responses against IAV remains unknown. Utilizing a murine model of IAV infection in mice lacking the IFN-lambda receptor (Ifnlr1−/−), we determined that IFN-lambda signaling is required for full induction of effector and memory CD8 T cell responses Ifnlr1−/− are significantly more susceptible to mortality following heterosubtypic IAV re-infection. This defect in the CD8 T cell response was not intrinsic to the T cells, but rather due to aberrant dendritic cell (DC) function in the absence of IFN-lambda signaling. Transcriptional analysis of conventional DCs (cDC) sorted from draining lymph nodes of IAV-infected mice revealed specific modulation of an immunoregulatory program in cDC from Ifnlr1−/−, but not WT mice. Indeed, we found IL-10 to be secreted only by Ifnlr1−/−, and not WT, BMDC following IAV infection. Addition of IL-10 to WT BMDC only partially recapitulated defects in DC maturation observed in Ifnlr1−/−, suggesting more additional pathways of regulation of DC by IFN-lambda. Our analysis further revealed shared and unique Ifnar1- and Ifnlr1-dependent transcriptional responses in DCs, highlighting the distinct role IFN-lambda plays in regulating DC function during IAV infection. Overall, these studies reveal a unique role for IFN-lambda programming of DCs to optimally activate protective CD8 T cell responses during influenza virus infection.