STING-Dependent Type I IFN Production Inhibits CellMediated Immunity to Listeria monocytogenes

Infection with Listeria monocytogenes strains that enter the host cell cytosol leads to a robust cytotoxic T cell response resulting in long-lived cell-mediated immunity (CMI). Upon entry into the cytosol, L. monocytogenes secretes cyclic diadenosine monophosphate (c-di-AMP) which activates the innate immune sensor STING leading to the expression of IFN- and co-regulated genes. In this study, we examined the role of STING in the development of protective CMI to L. monocytogenes. Mice deficient for STING or its downstream effector IRF3 restricted a secondary lethal challenge with L. monocytogenes and exhibited enhanced immunity that was MyD88-independent. Conversely, enhancing STING activation during immunization by co-administration of c-di-AMP or by infection with a L. monocytogenes mutant that secretes elevated levels of c-di-AMP resulted in decreased protective immunity that was largely dependent on the type I interferon receptor. These data suggest that L. monocytogenes activation of STING downregulates CMI by induction of type I interferon. Author Summary Current vaccines are successful at generating neutralizing antibodies, however there is a pressing medical need to find adjuvants that yield long-lived memory T cells. Immunization with the bacterium Listeria monocytogenes induces a robust protective immune response mediated by cytotoxic lymphocytes that are efficient at killing infected cells upon reinfection. When L. monocytogenes enters a cell, it secretes the small molecule cyclic diadenosine monophosphate (c-di-AMP), which activates the host protein STING leading to a type I interferon response. In this study, we tested whether STING activation plays a role in the generation of cytotoxic lymphocytes and protective immunity using a mouse immunization model. We found that in the absence of STING signaling mice restricted bacterial growth and maintained higher numbers of cytotoxic lymphocytes upon reinfection, whereas mice immunized in the presence of elevated levels of c-di-AMP were less protected. These results suggest that the inflammation induced by a bacterial pathogen can be detrimental to the development of adaptive immunity, which could provide new insights into vaccine development.