Prostaglandin E2 amplifies IL-17 production by γδ Tcells during barrier inflammation.

Abstract

Interleukin-17 (IL-17)-producing γδ (γδ17) Tcells are innate-like lymphocytes that contribute to protective anti-microbial responses but are also implicated in pathogenic inflammation at barrier sites. Understanding tissue-specific signals that regulate this subset is important to boost host defense mechanisms, but also to mitigate immunopathology. Here, we demonstrate that prostaglandin E2 (PGE2), a cyclooxygenase-dependent member of the eicosanoid family, directly enhances cytokine production by circulating and tissue-specific γδ17 Tcells invitro. Gain- and loss-of-function invivo approaches further reveal that although provision of PGE2 amplifies psoriasiform inflammation, ablation of host mPGES1-dependent PGE2 synthesis is dispensable for cutaneous γδ17 Tcell activation. By contrast, loss of endogenous PGE2 production or depletion of the gut microbiota compromises intestinal γδ17 Tcell responses and increases disease severity during experimental colitis. Together, our results demonstrate how a lipid mediator can synergize with tissue-specific signals to enhance innate lymphocyte production of IL-17 during barrier inflammation.