Prostaglandin E2 affects T cell responses through modulation of CD46 expression.

The complement regulator CD46 controls T cell activation and differentiation. 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) kinase family were involved in regulating CD46 expression at the T cell surface. We have investigated the role of prostaglandin E2 (PGE2), which binds to GPCRs, 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: i) addition of PGE2 strongly downregulates CD46 expression in activated T cells, ii) PGE2 differentially affects T cell activation, cytokine production and phenotype depending on the activation signals received by the T cells, iii) this was correlated with a distinct pattern of the EP2-EP4 PGE2 receptors induced, with EP4 being preferentially expressed upon CD46, and iv) addition of an EP4 antagonist could reverse the effects observed on cytokine production upon CD46 costimulation. These data demonstrate a novel role of the PGE2-EP4-GRK axis in CD46 functions, which might partly explain the diverse roles of PGE2 in T cell functions.