Prostaglandin E2 directly inhibits the conversion of inducible regulatory T cells through EP2 and EP4 receptors via antagonizing TGF-β signalling.

Marie Goepp,Shuh Narumiya,Chengcan Yao,You Zhou,Adriano G Rossi,Siobhan Crittenden

doi:10.1111/imm.13417

Marie Goepp, Shuh Narumiya + Show 4 more

Open Access

https://doi.org/10.1111/imm.13417

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Abstract

Regulatory T (Treg) cells are essential for control of inflammatory processes by suppressing effector T‐cell functions. The actions of PGE2 on the development and function of Treg cells, particularly under inflammatory conditions, are debated. In this study, we employed pharmacological and genetic approaches to examine whether PGE2 had a direct action on T cells to modulate de novo differentiation of Treg cells. We found that TGF‐β‐induced Foxp3 expression and iTreg cell differentiation in vitro is markedly inhibited by PGE2, which was mediated by the receptors EP2 and EP4. Mechanistically, PGE2‐EP2/EP4 signalling interrupts TGF‐β signalling during iTreg differentiation. Moreover, EP4 deficiency in T cells impaired iTreg cell differentiation in vivo. Thus, our results demonstrate that PGE2 negatively regulates iTreg cell differentiation through a direct action on T cells, highlighting the potential for selectively targeting the PGE2‐EP2/EP4 pathway to control T cell‐mediated inflammation.

Highlights

Regulatory T cells (Tregs) are a subset of T lymphocytes that play essential roles in the maintenance of immune homeostasis and in the control of inflammatory responses [1,2]
We found that prostaglandin E2 (PGE2) negatively regulated inducible regulatory T cell (Treg) (iTreg) cell differentiation in vitro by inhibiting transforming growth factor β (TGF-β)-driven Forkhead box P3 (Foxp3) induction through E prostanoid receptor 2 (EP2) and E prostanoid receptor 4 (EP4)
Our results have revealed that PGE2 directly acts on T cells to abrogate iTreg cell differentiation, which may contribute to foster T cell-mediated inflammation

Summary

Introduction

Regulatory T cells (Tregs) are a subset of T lymphocytes that play essential roles in the maintenance of immune homeostasis and in the control of inflammatory responses [1,2]. Treg cells actively suppress immune responses against autologous and foreign antigens in vitro and in vivo. Treg cells are characterized as expression of the surface marker CD25 (i.e., IL-2 receptor α chain, IL-2Rα) and the master transcription factor Forkhead box P3 (Foxp3) and produce the anti-inflammatory cytokine IL-10 [1]. Foxp controls both Treg cell development and their unique suppressive function [9–11]. Loss or mutation of Foxp expression links to a defective development of CD4+CD25+ Treg cells and in turn results in fatal autoimmune and inflammatory diseases, inducing a lymphoproliferative disorder in mice and leading to the IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome in human [12,13]

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