title: 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 toward a regulatory Tr1-like phenotype. The 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 RNA interference-based screening approach in primary T cells, we have identified that two members of the G protein-coupled receptor kinases were involved in regulating CD46 expression at the surface of activated cells. We have investigated the role of PGE(2), which binds to the E-prostanoid family of G protein-coupled receptors through four subtypes of receptors called EP 1-4, in the regulation of CD46 expression and function. Conflicting roles of PGE(2) in T cell functions have been reported, and the reasons for these apparent discrepancies are not well understood. We show that addition of PGE(2) strongly downregulates CD46 expression in activated T cells. Moreover, PGE(2) 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 PGE(2) receptors expressed, with EP4 being preferentially induced by CD46 activation. Indeed, addition of an EP4 antagonist could reverse the effects observed on cytokine production after CD46 costimulation. These data demonstrate a novel role of the PGE(2)-EP4 axis in CD46 functions, which might at least partly explain the diverse roles of PGE(2) in T cell functions.
authors.affiliation: Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Karoline
authors.initials: K
authors.lastname: Kickler
authors.forename: Kathryn
authors.initials: K
authors.lastname: Maltby
authors.forename: Siobhán
authors.initials: S
authors.lastname: Ni Choileain
authors.forename: Jillian
authors.initials: J
authors.lastname: Stephen
authors.forename: Sheila
authors.initials: S
authors.lastname: Wright
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
authors.forename: Henry N
authors.initials: HN
authors.lastname: Jabbour
authors.forename: Anne L
authors.initials: AL
authors.lastname: Astier
mesh_terms: D049109:Cell Proliferation; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism / Q000502:physiology*; D051606:G-Protein-Coupled Receptor Kinase 1 / Q000502:physiology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D051916:Membrane Cofactor Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D034622:RNA Interference / Q000276:immunology; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
chemical_list: C497857:CD46 protein, human; D051916:Membrane Cofactor Protein; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051606:G-Protein-Coupled Receptor Kinase 1; C496764:GRK1 protein, human; D015232:Dinoprostone