Prostaglandin E₂directly inhibits the conversion of inducible regulatory T cells through EP2 and EP4 receptors via antagonizing TGF-β signalling

Abstract

Background and Purpose: Regulatory T (Treg) cells are essential for control of inflammatory processes by suppressing Th1 and Th17 cells. The bioactive lipid mediator prostaglandin E2 (PGE2) promotes inflammatory Th1 and Th17 cells and exacerbates T cell-mediated autoimmune diseases. However, the actions of PGE2 on the development and function of Treg cells, particularly under inflammatory conditions, are debated. In this study, we examined whether PGE2 had a direct action on T cells to modulate de novo differentiation of Treg cells. Experimental Approach: We employed an in vitro T cell culture system of TGF-β-dependent Treg induction from naive T cells. PGE2 and selective agonists for its receptors, and other small molecular inhibitors were used. Mice with specific lack of EP4 receptors in T cells were used to assess Treg cell differentiation in vivo. Human peripheral blood T cells from healthy individuals were used to induce differentiation of inducible Treg cells. Key Results: TGF-β-induced Foxp3 expression and Treg cell differentiation in vitro was markedly inhibited by PGE2, which was due to interrupting TGF-β signalling. EP2 or EP4 agonism mimicked suppression of Foxp3 expression in WT T cells, but not in T cells deficient in EP2 or EP4, respectively. Moreover, deficiency of EP4 in T cells impaired iTreg cell differentiation in vivo. PGE2 also appeared to inhibit the conversion of human iTreg cells. Conclusion and Implications: Our results show a direct, negative regulation of iTreg cell differentiation by PGE2, highlighting the potential for selectively targeting the PGE2-EP2/EP4 pathway to control T cell-mediated inflammation.

Helminthic dehydrogenase drives PGE 2 and IL‐10 production in monocytes to potentiate Treg induction

“…Indeed, the expression and role of PGE 2 receptors EP2/4 and, thus, the regulation of cell behavior and immunological effects of PGE 2 (e.g., Treg induction) are complex and context‐dependent (disease, tissue, co‐signal). For instance, while PGE 2 has the potential to support Treg expansion by TGF‐ß‐Smad2/3 signaling (English et al , 2009; Cho et al , 2015), it has also been shown to inhibit this signal via stimulation of ERK1/2, PI3K/AKT, and 3’5’‐cAMP phosphorylation, which degrade Smad2/3 signaling (Thomas et al , 2007; Goepp et al , 2021). Whereas our settings suggest that induction of PGE 2 may contribute to a mechanism by which parasitic worms induce Tregs to control host immune attack, it may inhibit unwanted suppressive Treg activity in distinct immunological settings and tissue environments (e.g., tumor environment, intestine).…”

“…Finally, the suppressive effect of PGE 2 on immune cells is affected by TCR‐signaling. Thus, PGE 2 inhibited Treg conversion via EP2 and EP4 in co‐stimulation of murine splenic, colonic, and peripheral blood human naïve T cells with TGF‐ß in presence of TCR activators (αCD3/αCD28) and/or cytokines (IL‐2, IL‐12) (Narumiya et al , 1999; Fulton et al , 2006; Neil et al , 2008; Goepp et al , 2021). In our hand, with no TCR activators or co‐stimulation, PGE 2 rather supports TGF‐ß signaling (or vice‐versa) as the simultaneous inhibition of both TGF‐ß and PGE 2 signals synergistically prevented Treg induction.…”