Type I Interferon Signaling on Antigen-Presenting Cells Blunts Cell-Mediated Immunity Toward Listeria monocytogenes

Abstract

Listeria monocytogenes is a facultative intracellular pathogen that has been used for decades to understand mechanisms of bacterial pathogenesis and both innate and adaptive immunity. L. monocytogenes is a potent activator of CD8+ T-cell mediated immunity. Yet how the innate immune response to infection modulates CD8+ T-cell responses is incompletely understood. Here, we utilize an attenuated L. monocytogenes vaccine platform to understand the impact of two innate immune pathways, type I interferon and inflammasomes, on CD8+ T-cell responses using a combination of mutant mice and genetically engineered L. monocytogenes. IFNAR-/- mice had the most robust T-cell response, while Caspase-1-/- mice were not different from WT. We uncover a role for inflammasomes in the absence of type I interferon as Caspase-1-/-/IFNAR-/- mice had fewer T-cells than IFNAR-/-. IFNAR-/- had more than twice as many memory precursors, promoting enhanced protection from rechallenge. Importantly, increased memory precursor T-cell abundance did not come at the expense of short-lived effectors. Vaccines genetically modified to induce lower type I interferon production yielded enhanced T-cell responses. Deficits from type I interferon signaling are dendritic cell-intrinsic, rather than acting on T-cells, as IFNAR-/- dendritic cells induced two-fold more T-cell proliferation than WT in ex vivo T-cell proliferation assays. Thus, modulating type I IFN signaling during vaccination may lead to more potent T-cell-based vaccines. Importantly, this suggests innate immune signaling significantly impacts the CD8+ T-cell response and suggests CD8+ T-cell quantity and quality are important factors to consider during rational vaccine design.