Amplifying IFN-{gamma} Signaling in Dendritic Cells by CD11c-Specific Loss of SOCS1 Increases Innate Immunity to Infection while Decreasing Adaptive Immunity [INFECTIOUS DISEASE AND HOST RESPONSE]

Although prophylactic vaccines provide protective humoral immunity against infectious agents, vaccines that elicit potent CD8 T cell responses are valuable tools to shape and drive cellular immunity against cancer and intracellular infection. In particular, IFN-–polarized cytotoxic CD8 T cell immunity is considered optimal for protective immunity against intracellular Ags. Suppressor of cytokine signaling (SOCS)1 is a cross-functional negative regulator of TLR and cytokine receptor signaling via degradation of the receptor–signaling complex. We hypothesized that loss of SOCS1 in dendritic cells (DCs) would improve T cell responses by accentuating IFN-–directed immune responses. We tested this hypothesis using a recombinant Listeria monocytogenes vaccine platform that targets CD11c⁺ DCs in mice in which SOCS1 is selectively deleted in all CD11c⁺ cells. Unexpectedly, in mice lacking SOCS1 expression in CD11c⁺ cells, we observed a decrease in CD8⁺ T cell response to the L. monocytogenes vaccine. NK cell responses were also decreased in mice lacking SOCS1 expression in CD11c⁺ cells but did not explain the defect in CD8⁺ T cell immunity. We found that DCs lacking SOCS1 expression were functional in driving Ag-specific CD8⁺ T cell expansion in vitro but that this process was defective following infection in vivo. Instead, monocyte-derived innate TNF-α and inducible NO synthase–producing DCs dominated the antibacterial response. Thus, loss of SOCS1 in CD11c⁺ cells skewed the balance of immune response to infection by increasing innate responses while decreasing Ag-specific adaptive responses to infectious Ags.

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