Phagocytes produce prostaglandin E(2) in response to cytosolic Listeria monocytogenes

Listeria monocytogenes is an intracellular bacterium that elicits robust CD8(+) T-cell responses. Despite the ongoing development of L. monocytogenes-based platforms as cancer vaccines, our understanding of how L. monocytogenes drives robust CD8(+) T-cell responses remains incomplete. One overarching hypothesis is that activation of cytosolic innate pathways is critical for immunity, as strains of L. monocytogenes that are unable to access the cytosol fail to elicit robust CD8(+) T-cell responses and in fact inhibit optimal T-cell priming. Counterintuitively, however, activation of known cytosolic pathways, such as the inflammasome and type I IFN, lead to impaired immunity. Conversely, production of prostaglandin E(2) (PGE(2)) downstream of cyclooxygenase-2 (COX-2) is essential for optimal L. monocytogenes T-cell priming. Here, we demonstrate that vacuole-constrained L. monocytogenes elicit reduced PGE(2) production compared to wild-type strains in macrophages and dendritic cells ex vivo. In vivo, infection with wild-type L. monocytogenes leads to 10-fold increases in PGE(2) production early during infection whereas vacuole-constrained strains fail to induce PGE(2) over mock-immunized controls. Mice deficient in COX-2 specifically in Lyz2(+) or CD11c(+) cells produce less PGE(2), suggesting these cell subsets contribute to PGE(2) levels in vivo, while depletion of phagocytes with clodronate abolishes PGE(2) production completely. Taken together, this work demonstrates that optimal PGE(2) production by phagocytes depends on L. monocytogenes access to the cytosol, suggesting that one reason cytosolic access is required to prime CD8(+) T-cell responses may be to facilitate production of PGE(2).