PGE(2) controls Th17 and regulatory T cell function during intestinal immune responses

Abstract Eicosanoids, particularly prostaglandin E2 (PGE2), are critical molecules in the initiation and resolution of inflammation during immune responses. PGE2 is associated with modulating autoimmunity through altering the IL-23/IL-17 axis and regulatory T cells, whose balance is critical for controlling pathogenic T cells. The inducible microsomal prostaglandin E synthase 1 (mPGES1) is a membrane enzyme that regulates local PGE2 levels and is highly expressed at sites of inflammation. Hematopoietic and stromal cells express mPGES1, but its role in T cell function and intestinal biology remains underappreciated. Th17 polarized cells produce 10-fold more PGE2 than Th1 polarized cells, and this PGE2 production is mPGES1-dependent. Interestingly, high concentrations of PGE2 can shift the production from IL-17A to IFNg during Th17 polarization, and PGE2 promotes more cell proliferation and cytokine production in Th1 than in Th17 cells. Sensing of PGE2 at physiological concentrations through its EP4 receptor proved to be critical to inhibit the generation of iTregs but not Th1 or Th17 cells. In the colon, we observed that different inflammatory insults induce different PGE2 production levels, with concomitant modulation of T cell responses in the mesenteric lymph nodes. Furthermore, mPGES1 displayed opposite effects on pathogenic and regulatory T cells in the T-cell transfer colitis model, with mPGES1 deficiency limiting intestinal damage driven by effector T cells, but enhancing de novo generation of Tregs and increasing colonic lamina propria homing of CD4+FoxP3+ cells. Taken together, these data demonstrate the pleiotropic and context-dependent actions of mPGES1 and PGE2 in intestinal inflammation and immunity.