Prostaglandin E2 Affects T Cell Responses through Modulation of CD46 Expression

Abstract

The ubiquitous protein CD46, a regulator of complement activity, promotes T cell activation and differentiation towards a regulatory Tr1-like phenotype. CD46-mediated differentiation pathway is defective in several chronic inflammatory diseases, underlying the importance of CD46 in controlling T cell function and the need to understand its regulatory mechanisms. Using an RNAi-based screening approach in primary T cells, we have identified that two members of the G-protein coupled receptor (GPCR) kinases were involved in regulating CD46 expression at the surface of activated cells. We have investigated the role of prostaglandin E2 (PGE2), which binds to the E-prostanoid family of GPCRs through four subtypes of receptors called EP1-4, in the regulation of CD46 expression and function. Conflicting roles of PGE2 in T cell functions have been reported, and the reasons for these apparent discrepancies are not well understood. We show that addition of PGE2 strongly downregulates CD46 expression in activated T cells. Moreover, PGE2 differentially affects T cell activation, cytokine production and phenotype depending on the activation signals received by the T cells. This was correlated with a distinct pattern of the PGE2 receptors induced, with EP4 being preferentially induced by CD46 activation. Indeed, addition of an EP4 antagonist could reverse the effects observed on cytokine production observed following CD46 costimulation. These data demonstrate a novel role of the PGE2-EP4-GRK axis in CD46 functions, which might at least partly explain the diverse roles of PGE2 in T cell functions.

IgE and Mast Cells

“…Tumor necrosis factor (TNF) α, histamine, and proteases are immediately available upon degranulation and act to recruit neutrophils, T cells, and B cells (Galli & Tsai, 2012). Rapid de novo synthesis of leukotrienes and prostaglandins supports chemotaxis of various cell types and also influences antigen-presenting cell (APC) function and CD4 + T cell proliferation and differentiation (Boniface et al, 2009;Chen et al, 2009;Kickler et al, 2012;Krause et al, 2009;Yao et al, 2013). Cytokines produced by mast cells have the potential to significantly influence developing immune responses, with TNFα, IL-1, IL-4, IL-5, IL-6, IL-10, IL-12, and IL-13 all being capable of altering B and/or CD4 + T cell differentiation (Galli, Grimbaldeston, et al, 2008).…”

The Prostanoid EP4 Receptor and Its Signaling Pathway

“…A recent study demonstrated that CD46 activation induced EP4 expression and caused a decrease in the IL-10/IFN-g ratio in T cells, and that an EP4 antagonist reversed this effect on cytokine production after CD46 stimulation (Kickler et al, 2012). Nataraj et al (2001) showed mRNA expression of EP1, EP2, and EP4, but not EP3, on splenic T cells and B cells in mice.…”

Prostaglandin E2 Inhibition of IL-27 Production in Murine Dendritic Cells: A Novel Mechanism That Involves IRF1

“…Tumor-derived COX2/PGE2 was shown to promote Foxp3 + Treg and Foxp3 - Tr1 cells in cancer (63–67). In contrast, PGE2 inhibits the differentiation of non-tumor murine Foxp3 + Treg and of CD46-induced Tr1 cells (68, 69). …”