Inflammasome-associated inflammation inhibits cell-mediated immune responses to Listeria monocytogenes

Abstract

Abstract Listeria monocytogenes is a genetically tractable Gram-positive intracellular bacterium that activates a robust cell-mediated immune response capable of breaking self-tolerance. These properties contribute to its success as a cancer immunotherapeutic platform; however, despite these attributes, the specific mechanisms by which L. monocytogenes stimulates a robust adaptive immune response remain largely unknown. We hypothesized that cytosolic innate immune activation, specifically inflammasome activation, by L. monocytogenes would be critical for triggering a robust CD8+ T-cell response. Surprisingly, we found that inflammasome activation impairs the induction of antigen specific T-cells and ultimately the generation of protective immunity. To determine if this phenomenon is unique to inflammasome-induced pyroptosis or a general outcome of pathogen induced host cell death, we designed strains of L. monocytogenes to uniquely activate pyroptosis, necrosis, or apoptosis. Contrary to previous studies of immunity in the context of sterile cell death, pathogen induced pyroptosis, necrosis and apoptosis each impaired the generation of cell-mediated immunity. Importantly, the mechanism of impairment was unique for each form of cell death, although in each case it was independent of dendritic cell depletion or deficits in antigen presentation. Apoptosis and necrosis impaired dendritic cell co-stimulatory molecule expression, while the pyroptotic inflammatory milieu independently impaired the generation of cell-mediated immunity. These results suggest that inhibition of inflammasome activation, or specifically certain inflammatory components, is critical for the success of L. monocytogenes immunotherapy.