P-240 CD4+ T Cell-intrinsic PGE2 Production Alters Their Colitogenic and Suppressive Potential

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The integration of inflammatory signals is paramount in controlling the intensity and duration of immune responses. Eicosanoids, particularly prostaglandin E2 (PGE2), are critical molecules in the initiation and resolution of inflammation and in the transition from innate to acquired immune responses. Additionally, PGE2 is associated with modulating autoimmune features through altering the IL-23/IL-17 axis and regulatory T cell development, whose balance is critical for keeping potential pathogenic T cell responses under control. It is still unclear how PGE2 affects T cell differentiation and function in the intestines and during colitis. Microsomal prostaglandin E synthase 1 (mPGES-1) is a membrane enzyme that controls local PGE2 levels and is highly expressed at sites of inflammation. mPGES-1 is part of the PGE2 biosynthetic pathway and it controls PGE2 concentrations during inflammation. We hypothesize that mPGES1 plays a critical role in lymphoid and non-lymphoid intestinal tissues in controlling inflammatory responses, especially in the function of regulatory and pathogenic T cell responses.


We performed Th17 polarization assays with freshly isolated naïve T cells (CD4+CD44−CD62L+). We also sorted different T cell populations from primary lymphoid organs for subsequent RT-PCR analysis of interest, like T cell fate decision, PGE2-receptors, PG metabolism and inflammatory markers. Using LC-MS and ELISA we analyzed prostaglandin production by different T cells and intestines upon different conditions that lead to colonic inflammation. Mouse models of colitis (Rag−/− transfer model of T-cell driven colitis, C. rodentium infection, C. difficile infection and DSS) were used to examine regulatory and pathogenic T cell function and cell tropism to the intestinal tissues by flow cytometry.


We found that mPGES1−/− naïve T cells showed a significant decrease in tgfbr1, ptger2 and ptger4 (PGE2 receptors EP2 and EP4) expression compared with WT T cells. Since TGF-b is a key cytokine for the generation of both regulatory and Th17 cells we addressed the effect of mPGES-1 deficiency during Th17 and Treg cell responses. We observed that mPGES1−/− is necessary for PGE2 production under activation of T cells and Th1/Th17 polarizing conditions, but exogenous addition of PGE2 can shift the production of IL-17A to IFNg. In vitro activation also showed that CD4+CD25+ cells were less capable of secreting PGE2 than CD4+CD25−cells. Furthermore, distinct colitogenic insults differed in their induction of colon PGE2 production, with bacterial infectious colitis being the most PGE2-promoting event. In the Rag−/− adoptive T cell transfer colitis model, mPGES1−/− CD4+CD25+ cells showed an increased tropism of CD4+FoxP3+ cells in the colonic lamina propria when compared to mice transferred with WT CD4+CD25+ cells. Additionally, mPGES1−/− CD4+CD25−cells were less colitogenic than their WT counterparts.


T cells can produce PGE2 in large quantities. Endogenous mPGES-1-mediated production of PGE2 by T cells modulates both IL-17A and IFNg responses. Intestinal inflammatory insults are distinctively able to induce PGE2 in the colon, and also activate different compensatory mechanisms to maintain PGE2 levels in absence of mPGES-1. In vivo T cell deficiency of mPGES-1 decreases regulatory T cell seeding of the colonic lamina propria and pathogenic potential during colitis.

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