mPGES1-Dependent Prostaglandin E2 (PGE2) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE2 Production [INNATE IMMUNITY AND INFLAMMATION]

The integration of inflammatory signals is paramount in controlling the intensity and duration of immune responses. Eicosanoids, particularly PGE₂, are critical molecules in the initiation and resolution of inflammation and in the transition from innate to acquired immune responses. Microsomal PGE synthase 1 (mPGES1) is an integral membrane enzyme whose regulated expression controls PGE₂ levels and is highly expressed at sites of inflammation. PGE₂ is also associated with modulation of autoimmunity through altering the IL-23/IL-17 axis and regulatory T cell (Treg) development. During a type II collagen–CFA immunization response, lack of mPGES1 impaired the numbers of CD4⁺ regulatory (Treg) and Th17 cells in the draining lymph nodes. Ag-experienced mPGES1^–/– CD4⁺ cells showed impaired IL-17A, IFN-, and IL-6 production when rechallenged ex vivo with their cognate Ag compared with their wild-type counterparts. Additionally, production of PGE₂ by cocultured APCs synergized with that of Ag-experienced CD4⁺ T cells, with mPGES1 competence in the APC compartment enhancing CD4⁺ IL-17A and IFN- responses. However, in contrast with CD4⁺ cells that were Ag primed in vivo, exogenous PGE₂ inhibited proliferation and skewed IL-17A to IFN- production under Th17 polarization of naive T cells in vitro. We conclude that mPGES1 is necessary in vivo to mount optimal Treg and Th17 responses during an Ag-driven primary immune response. Furthermore, we uncover a coordination of autocrine and paracrine mPGES1-driven PGE₂ production that impacts effector T cell IL-17A and IFN- responses.

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