The role of Prostaglandin E2 in Listeria monocytogenes induced CD8+ T-cell priming

Abstract: Recognition of invading pathogens by the innate immune system triggers a series of signaling cascades that together program an appropriate adaptive immune response. Listeria monocytogenes is a Gram positive, intracellular pathogen that triggers robust innate immune responses upon escape from the phagosome into the host cell cytosol. Cytosolic innate immune recognition of L. monocytogenes ultimately results in priming of a robust protective immune response mediated by CD8+ T-cells. We recently demonstrated that production of the eicosanoid prostaglandin E2 following L. monocytogenes escape to the cytosol is essential for optimal CD8+ T-cell priming. How PGE2 is induced in response to cytosolic L. monocytogenes and how it subsequently promotes cell mediated immunity are currently unknown. We will take an unbiased approach to identify bacterial determinants of PGE2 induction using an established bacterial transposon mutant screen. In parallel we will use ex vivo dendritic cell-T-cell co- culture models to define the signaling pathways and cell types upon which PGE2 acts to promote CD8+ T-cell priming. Finally, using both pharmacologic agonists and antagonists as well as tissue specific PGE2 receptor knockout mice we will assess the role of specific PGE2 signaling pathways in CD8+ T- cell mediated protective immunity. Upon completion of these aims we will have identified how phagocytes produce PGE2 in response to cytosolic L. monocytogenes and will have identified bacterial mutants that induce altered levels of PGE2. We will have determined how PGE2 modulates dendritic cells and/or T-cell signaling to promote CD8+ T-cell priming and cell mediated immunity. Finally, we will have identified small molecules that improve T-cell responses in combination with L. monocytogenes-based vaccines. Future studies will focus on determining the conservation of PGE2 production as a response to cytosolic bacterial infection and whether PGE2 signaling promotes immunity in the context of L.monocytogenes stimulated anti-tumor immunity. Additional future studies will use the information generated here to determine if altering PGE2 signaling could improve the generation of CD8+ T-cells in response to other vaccine platforms such as mRNA-based vaccines.