mPGES-1-Mediated Production of PGE2 and EP4 Receptor Sensing Regulate T Cell Colonic Inflammation

Abstract

PGE₂ is a lipid mediator of the initiation and resolution phases of inflammation, as well as a regulator of immune system responses to inflammatory events. PGE₂ is produced and sensed by T cells, and autocrine or paracrine PGE₂ can affect T cell phenotype and function. In this study, we use a T cell-dependent model of colitis to evaluate the role of PGE₂ on pathological outcome and T-cell phenotypes. CD4⁺ T effector cells either deficient in mPGES-1 or the PGE₂ receptor EP4 are less colitogenic. Absence of T cell autocrine mPGES1-dependent PGE₂ reduces colitogenicity in association with an increase in CD4⁺RORγt⁺ cells in the lamina propria. In contrast, recipient mice deficient in mPGES-1 exhibit more severe colitis that corresponds with a reduced capacity to generate FoxP3⁺ T cells, especially in mesenteric lymph nodes. Thus, our research defines how mPGES-1-driven production of PGE₂ by different cell types in distinct intestinal locations impacts T cell function during colitis. We conclude that PGE₂ has profound effects on T cell phenotype that are dependent on the microenvironment.

Keywords: IBD–inflammatory bowel diseases; PGE2; T cell; Th17 & Tregs cells; Th17 activation; Treg = regulatory T cell; colitis; inflammation immunomodulation.