Abstract

Prostaglandin E2 (PGE2), a major lipid mediator abundant at inflammatory sites, acts as a proinflammatory agent in models of inflammatory/autoimmune diseases by promoting CD4 Th1/Th17 differentiation. Regulatory T cells, including the IL-10 producing Tr1 cells counterbalance the proinflammatory activity of effector Th1/Th17 cells. Tr1 cell differentiation and function are induced by IL-27, and depend primarily on sustained expression of c-Maf in addition to AhR and Blimp-1. In agreement with the in vivo proinflammatory role of PGE2, here we report for the first time that PGE2 inhibits IL-27-induced differentiation and IL-10 production of murine CD4+CD49b+LAG-3+Foxp3- Tr1 cells. The inhibitory effect of PGE2 was mediated through EP4 receptors and induction of cAMP, leading to a significant reduction in c-Maf expression. Although PGE2 reduced IL-21 production in differentiating Tr1 cells, its inhibitory effect on Tr1 differentiation and c-Maf expression also occurred independent of IL-21 signaling. PGE2 did not affect STAT1/3 activation, AhR expression and only marginally reduced Egr-2/Blimp-1 expression. The effect of PGE2 on CD4+CD49b+LAG-3+ Tr1 differentiation was not associated with either induction of Foxp3 or IL-17 production, suggesting a lack of transdifferentiation into Foxp3+ Treg or effector Th17 cells. We recently reported that PGE2 inhibits the expression and production of IL-27 from activated conventional dendritic cells (cDC) in vivo and in vitro. The present study indicates that PGE2 also reduces murine Tr1 differentiation and function directly by acting on IL-27-differentiating Tr1 cells. Together, the ability of PGE2 to inhibit IL-27 production by cDC, and the direct inhibitory effect on Tr1 differentiation mediated through reduction in c-Maf expression, represent a new mechanistic perspective for the proinflammatory activity of PGE2.

Highlights

  • The proinflammatory activity of effector T cells is counterbalanced by regulatory T cell subsets, i.e. the Foxp3+ regulatory T cells (Treg) and the IL-10 producing regulatory type 1 cells (Tr1)

  • To determine whether Prostaglandin E2 (PGE2) affects Tr1 differentiation solely through the reduction in endogenous IL-27, we tested its effect in the presence and absence of exogenously added IL-27

  • In agreement with the in vivo proinflammatory role of PGE2, here we report for the first time that PGE2 inhibits the IL-27-induced differentiation of regulatory Tr1 cells

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Summary

Introduction

The proinflammatory activity of effector T cells is counterbalanced by regulatory T cell subsets, i.e. the Foxp3+ regulatory T cells (Treg) and the IL-10 producing regulatory type 1 cells (Tr1). Both thymus-derived tTreg and peripherally-induced pTreg are characterized by constitutive expression of CD25 and of the master transcription factor Foxp, and are essential to maintain. The immunosuppressive role of IL-27 has been described in various inflammatory disease models, with IL-27R deficient mice exhibiting excessive inflammation, and IL-27 treatment inducing IL-10 and suppressing IL-17 production [9, 10]. Tr1 cells were generated in vivo following intranasal administration of anti-CD3 in a process dependent on IL-27 production by upper airway resident DC [17]

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