IFN-lambda modulates dendritic cells to facilitate protective T cell immunity during influenza A virus infection

Abstract

Abstract Influenza A virus (IAV) remains a global health burden for which therapeutic and vaccination strategies to limit infection and drive robust, protective immune responses are still needed. Type III interferon (IFN), IFN-lambda (IFNλ), restricts IAV in vivo compared to type I IFN. IFNλ signaling in both epithelial cells and neutrophils contribute to this innate antiviral control of IAV. However, the contribution of IFNλ to program protective adaptive immune reposes against IAV has not been defined. To investigate the role of IFNλ in programming effective immunity against IAV, we evaluated responses in lungs and lymph nodes (LN) of WT and IFNλ receptor knock out (Ifnlr−/−) mice following IAV infection. Ifnlr−/− mice had significantly reduced pulmonary IAV-specific CD8 T cell responses during primary infection compared to WT that resulted in loss of protection against subsequent heterosubtypic IAV re-challenge. We found that this defect in the T cell response was not an intrinsic T cell defect, but instead was due to disruption of IFNλ-dependent dendritic cell (DC) function, as confirmed by infection of conditional Ifnlr−/− mice. Analysis of cell function revealed BMDCs respond to IFNλ, and that Ifnlr−/− DCs are defective in antigen uptake, processing, cell maturation, and cell migration. Transcriptomic analysis of DCs sorted from LN show that IFNλ (but not type I IFN) signaling is essential to modulate an IL-10 immunoregulatory program during IAV infection that links with the reduced function observed in Ifnlr−/− DCs. Our studies reveal a novel role for IFNλ in programming DCs for effective T cell actions to control IAV infection that may be broadly applicable to development of therapeutics against respiratory and other viral infections.