Interferon-lambda modulates dendritic cell IL-10 production and CD8 T cell immunity during influenza A virus infection

Abstract

Abstract Influenza A virus (IAV) infection remains a major global health burden, requiring development of novel strategies to limit infection and drive durable protective immunity. Type III interferon (IFN), IFN-lambda, plays an important role in regulating IAV infection and immunity, but it’s contribution to regulating adaptive immunity remains less understood. Our previous research found mice lacking the IFN-lambda receptor (Ifnlr1−/−) are more susceptible to heterosubtypic rechallenge with influenza A virus. Ifnlr1−/−mice also have reduced effector and memory IAV-specific CD8 T cells compared to WT, highlighting a unique role for IFN-lambda in regulating protective CD8 T cell immunity against IAV. However, this defect in the CD8 T cell response was not T cell-intrinsic, but rather due to aberrant dendritic cell (DC) function in the absence of IFN-lambda signaling. RNA-Seq analysis of DC from the draining lymph nodes of mice following IAV infection revealed enhancement of an immunosuppressive network containing IL-10 in Ifnlr1−/−not present in WT. We hypothesize that IFN-lambda suppresses IL-10, playing a crucial role in regulation of protective CD8 T cell responses against IAV. Our results demonstrate IL-10 production is increased in bone marrow-derived DC (BMDC) in vitro and CD103 +DC in vivo following IAV infection in Ifnlr1−/−compared to WT. Ongoing experiments will unravel the contribution of IFN-lambda regulated IL-10 in regulation of CD8 T cell responses during IAV infection in vivo. Overall, understanding the mechanisms by which IFN-lambda signaling regulates DC function and protective CD8 T cell immunity will inform therapeutic potential of this cytokine during respiratory virus infection. Supported by NIH grant K22 AI146141