title: Efficient T-cell priming and activation requires signaling through prostaglandin E2 (EP) receptors.
abstract: Understanding the regulation of T-cell responses during inflammation and auto-immunity is fundamental for designing efficient therapeutic strategies against immune diseases. In this regard, prostaglandin E2 (PGE2) is mostly considered a myeloid-derived immunosuppressive molecule. We describe for the first time that T cells secrete PGE2 during T-cell receptor stimulation. In addition, we show that autocrine PGE2 signaling through EP receptors is essential for optimal CD4(+) T-cell activation in vitro and in vivo, and for T helper 1 (Th1) and regulatory T cell differentiation. PGE2 was found to provide additive co-stimulatory signaling through AKT activation. Intravital multiphoton microscopy showed that triggering EP receptors in T cells is also essential for the stability of T cell-dendritic cell (DC) interactions and Th-cell accumulation in draining lymph nodes (LNs) during inflammation. We further demonstrated that blocking EP receptors in T cells during the initial phase of collagen-induced arthritis in mice resulted in a reduction of clinical arthritis. This could be attributable to defective T-cell activation, accompanied by a decline in activated and interferon-γ-producing CD4(+) Th1 cells in draining LNs. In conclusion, we prove that T lymphocytes secret picomolar concentrations of PGE2, which in turn provide additive co-stimulatory signaling, enabling T cells to attain a favorable activation threshold. PGE2 signaling in T cells is also required for maintaining long and stable interactions with DCs within LNs. Blockade of EP receptors in vivo impairs T-cell activation and development of T cell-mediated inflammatory responses. This may have implications in various pathophysiological settings.
authors.affiliation: Department of Molecular Biology, Centre for Molecular Biology Severo Ochoa, Universidad Autónoma de Madrid-CSIC, Madrid, Spain.
authors.forename: Vinatha
authors.initials: V
authors.lastname: Sreeramkumar
authors.affiliation: Department of Immunobiology and Lymphocyte Migration, Theodor Kocher Institute, University of Bern, Bern, Switzerland.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Hons
authors.affiliation: Department of Molecular Biology, Centre for Molecular Biology Severo Ochoa, Universidad Autónoma de Madrid-CSIC, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Punzón
authors.affiliation: Department of Immunobiology and Lymphocyte Migration, Theodor Kocher Institute, University of Bern, Bern, Switzerland.
authors.forename: Jens V
authors.initials: JV
authors.lastname: Stein
authors.affiliation: Department of Vascular Biology and Inflammation, Spanish National Centre for Cardiovascular Research 'Carlos III', CNIC, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Sancho
authors.affiliation: Department of Molecular Biology, Centre for Molecular Biology Severo Ochoa, Universidad Autónoma de Madrid-CSIC, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Fresno
authors.affiliation: Department of Molecular Biology, Centre for Molecular Biology Severo Ochoa, Universidad Autónoma de Madrid-CSIC, Madrid, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Cuesta
mesh_terms: D000818:Animals; D001168:Arthritis / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation; D049109:Cell Proliferation; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000378:metabolism; D018345:Mice, Knockout; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D015854:Up-Regulation
chemical_list: D018836:Inflammation Mediators; D007376:Interleukin-2; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone