mPGES1-Dependent Prostaglandin E-2 (PGE(2)) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE(2) Production

作者：Maseda Damian; Johnson Elizabeth M.; Nyhoff Lindsay E.; Baron Bridgette; Kojima Fumiaki; Wilhelm Ashley J.; Ward Martin R.; Woodward Jerold G.; Brand David D.; Crofford Leslie J.^*

来源：The Journal of Immunology, 2018, 200(2): 725-736.

DOI：10.4049/jimmunol.1601808

The integration of inflammatory signals is paramount in controlling the intensity and duration of immune responses. Eicosanoids, particularly PGE(2), 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 PGE(2) levels and is highly expressed at sites of inflammation. PGE(2) 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-gamma, and IL-6 production when rechallenged ex vivo with their cognate Ag compared with their wild-type counterparts. Additionally, production of PGE(2) 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-gamma responses. However, in contrast with CD4(+) cells that were Ag primed in vivo, exogenous PGE(2) inhibited proliferation and skewed IL-17A to IFN-gamma 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 PGE(2) production that impacts effector T cell IL-17A and IFN-gamma responses.

• 出版日期2018-1-15