Prostaglandin E2induction by cytosolicListeria monocytogenesin phagocytes is necessary for optimal T-cell priming
Authors: McDougal Courtney E. , Morrow Zachary T. , Kim Seonyoung , Carter Drake , Stevenson David M. , Amador-Noguez Daniel , Miller Mark J. , Sauer John-Demian 
Published: March 2021

Listeria monocytogenesis an intracellular bacterium that elicits robust CD8+T-cell responses. Despite the ongoing development ofL. monocytogenes-based platforms as cancer vaccines, our understanding of howL. monocytogenesdrives robust CD8+T-cell responses remains incomplete. One overarching hypothesis is that activation of cytosolic innate pathways is critical for immunity, as strains ofL. monocytogenesthat 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. Here, we describe a cytosol-dependent response that is critical for immunity toL. monocytogenes, namely production of prostaglandin E2(PGE2) downstream of cyclooxygenase-2 (COX-2). Vacuole-constrainedL. monocytogeneselicit reduced PGE2production compared to wild-type strains in macrophages and dendritic cellsex vivo.In vivo,infection with wild-typeL. monocytogenesleads to 10-fold increases in PGE2production early during infection whereas vacuole-constrained strains fail to induce PGE2over mock-immunized controls. Mice deficient in COX-2 specifically in Lyz2+or CD11c+cells produce less PGE2, suggesting these cell subsets contribute to PGE2levelsin vivo,while depletion of phagocytes with clodronate abolishes PGE2production completely. Taken together, this work identifies the first known cytosol-dependent innate immune response critical for generating CD8+T-cell responses toL. monocytogenes,suggesting that one reason cytosolic access is required to prime CD8+T-cell responses may be due to induction of PGE2.

Author summary

L. monocytogenesis an intracellular bacterial pathogen that generates robust cell-mediated immune responses. Due to this robust induction,L. monocytogenesis used as both a model to understand how CD8+ T-cells are primed, as well as a platform for cancer immunotherapy vaccines.L. monocytogenesmust enter the cytosol of an infected host cell to stimulate robust T-cell responses, however, which cytosolic innate pathway(s) contribute to T-cell priming remains unclear. Here, we define COX-2 dependent PGE2production as the first cytosol-dependent innate immune response critical for immunity toL. monocytogenes. We found thatex vivoPGE2production by macrophages and dendritic cells is partially dependent on cytosolic access, as vacuole-constrained strains ofL. monocytogeneselicit reduced PGE2.In vivo,cytosolic access is essential for PGE2production.L. monocytogeneselicits a 10-fold increase in PGE2production, whereas strains ofL. monocytogenesthat cannot access the cytosol fail to elicit PGE2compared to mock immunized mice. Furthermore, CD11c+and Lyz2+cells contribute to PGE2productionin vivo, as mice deficient in COX-2 in these cell subsets have impaired PGE2production. Taken together, our work identifies the first known cytosol-dependent pathway that is critical for generating immunity toL. monocytogenes.