Regulatory T cell differentiation and Th17 T cell function are regulated by mPGES-1-dependent PGE2 (IRC11P.424)

Abstract Prostaglandin E2 (PGE2) is a lipid mediator that regulates inflammatory and immune responses. PGE2 has pleiotropic effects on many cell types, but it is still unclear how it affects T cell differentiation and function. The mPGES1 enzyme is part of the PGE2 biosynthetic pathway and, due to its inducible nature, it controls PGE2 concentrations during activation of the inflammatory program. Absence of mPGES1 causes shunting to alternate prostaglandins and changes the characteristics of the inflammatory response. We identified that, compared to WT, naïve T cells from mice with genetic deletion of mPGES1 express a 4-fold lower level of TFGbR1 and 8-fold lower level of the EP4 PGE receptor. Since TGF-b is a key cytokine for the generation of both regulatory and Th17 cells we addressed the effect of mPGES1 deficiency during in vitro T cell polarization. We observed that mPGES1-/- naïve CD4+ T cells generate less iTreg cells, while Th17 commitment is unaffected. However, when stimulating T cells with anti-CD3/CD28 from mice following immunization with type II collagen (CII), mPGES1-/- CD4+ T cells were unable to secrete IL-17A compared to its WT T cell counterparts. Furthermore, in-vivo antigen-specific Th17 responses from CII immunized mice were also impaired, showing a decrease in IL17A production in mPGES1-/- T cells compared to WT. Hence, endogenous production and sensing of PGE2 modulates T cell differentiation possibly by altering TGF-b responses.