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 mPGES12/2 CD4+ cells showed impaired IL-17A, IFN-g, 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-g responses. However, in contrast with CD4+ cells that were Ag primed in vivo, exogenous PGE2 inhibited proliferation and skewed IL-17A to IFN-g 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-g responses.
|Number of pages||12|
|Journal||Journal of Immunology|
|State||Published - Jan 15 2018|
Bibliographical noteFunding Information:
This work was supported by an R01 grant from the National Institutes of Health (5R01AR049010-11 to L.J.C.) and a Career Development Award from the Crohn’s and Colitis Foundation of America (to D.M.). The Vanderbilt Hormone Assay Core is supported by National Institutes of Health Grants DK0596367 and DK020593.
This work was supported by an R01 grant from the National Institutes of Health (5R01AR049010-11 to L.J.C.) and a Career Development Award from the Crohn's and Colitis Foundation of America (to D.M.). The Vanderbilt Hormone Assay Core is supported by National Institutes of Health Grants DK0596367 and DK020593.
Copyright © 2018 by The American Association of Immunologists, Inc.
ASJC Scopus subject areas
- Immunology and Allergy