title: Upholding the T cell immune-regulatory function of CD31 inhibits the formation of T/B immunological synapses in vitro and attenuates the development of experimental autoimmune arthritis in vivo.
abstract: CD31, a trans-homophilic inhibitory receptor expressed on both T- and B-lymphocytes, drives the mutual detachment of interacting leukocytes. Intriguingly, T cell CD31 molecules relocate to the immunological synapse (IS), where the T and B cells establish a stable interaction. Here, we show that intact CD31 molecules, which are able to drive an inhibitory signal, are concentrated at the periphery of the IS but are excluded from the center of the IS. At this site, were the cells establish the closest contact, the CD31 molecules are cleaved, and most of the extracellular portion of the protein, including the trans-homophilic binding sites, is shed from the cell surface. T cells lacking CD31 trans-homophilic binding sites easily establish stable interactions with B cells; at the opposite, CD31 signaling agonists inhibit T/B IS formation as well as the ensuing helper T cell activation and function. Confocal microscopy and flow cytometry analysis of experimental T/B IS shows that the T cell inhibitory effects of CD31 agonists depend on SHP-2 signaling, which reduces the phosphorylation of ZAP70. The analysis of synovial tissue biopsies from patients affected by rheumatoid arthritis showed that T cell CD31 molecules are excluded from the center of the T/B cell synapses in vivo. Interestingly, the administration of CD31 agonists in vivo significantly attenuated the development of the clinical signs of collagen-induced arthritis in DBA1/J mice. Altogether, our data indicate that the T cell co-inhibitory receptor CD31 prevents the formation of functional T/B immunological synapses and that therapeutic strategies aimed at sustaining CD31 signaling will attenuate the development of autoimmune responses in vivo.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U1148, "Laboratory of Vascular Translational Science", F-75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, F-75018 Paris, France; Département Hospitalo-Universitaire DHU "FIRE", F-75018 Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Clement
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U1148, "Laboratory of Vascular Translational Science", F-75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, F-75018 Paris, France; Département Hospitalo-Universitaire DHU "FIRE", F-75018 Paris, France.
authors.forename: Giulia
authors.initials: G
authors.lastname: Fornasa
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U1148, "Laboratory of Vascular Translational Science", F-75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, F-75018 Paris, France; Département Hospitalo-Universitaire DHU "FIRE", F-75018 Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Loyau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U1148, "Laboratory of Vascular Translational Science", F-75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, F-75018 Paris, France; Département Hospitalo-Universitaire DHU "FIRE", F-75018 Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Morvan
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U1148, "Laboratory of Vascular Translational Science", F-75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, F-75018 Paris, France; Département Hospitalo-Universitaire DHU "FIRE", F-75018 Paris, France.
authors.forename: Francesco
authors.initials: F
authors.lastname: Andreata
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U1148, "Laboratory of Vascular Translational Science", F-75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, F-75018 Paris, France; Département Hospitalo-Universitaire DHU "FIRE", F-75018 Paris, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Guedj
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U1148, "Laboratory of Vascular Translational Science", F-75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, F-75018 Paris, France; Département Hospitalo-Universitaire DHU "FIRE", F-75018 Paris, France.
authors.forename: Jamila
authors.initials: J
authors.lastname: Khallou-Laschet
authors.affiliation: Institut Curie, Section Recherche, Inserm U932, F-75005 Paris, France.
authors.forename: Paola
authors.initials: P
authors.lastname: Larghi
authors.affiliation: Inserm U1016, Institut Cochin, F-75014 Paris, France; Centre National de la Recherche Scientifique, UMR8104, F-75014 Paris, France; Université Paris Descartes, Paris F-75014, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Le Roux
authors.affiliation: Inserm U1016, Institut Cochin, F-75014 Paris, France; Centre National de la Recherche Scientifique, UMR8104, F-75014 Paris, France; Université Paris Descartes, Paris F-75014, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Bismuth
authors.affiliation: Inserm U987, Faculté des Sciences de la Santé "Simone Veil", F-78180 Saint-Quentin-en-Yvelines, France; Laboratoire d'Excellence "Inflamex", F-75018 Paris, France; Université Versailles-Saint-Quentin, F-78180 Saint-Quentin-en-Yvelines, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Chiocchia
authors.affiliation: Institut Curie, Section Recherche, Inserm U932, F-75005 Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Hivroz
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Debra K
authors.initials: DK
authors.lastname: Newman
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U1148, "Laboratory of Vascular Translational Science", F-75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, F-75018 Paris, France; Département Hospitalo-Universitaire DHU "FIRE", F-75018 Paris, France.
authors.forename: Antonino
authors.initials: A
authors.lastname: Nicoletti
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm), U1148, "Laboratory of Vascular Translational Science", F-75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, F-75018 Paris, France; Département Hospitalo-Universitaire DHU "FIRE", F-75018 Paris, France. Electronic address: giuseppina.caligiuri@inserm.fr.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Caligiuri
mesh_terms: D000368:Aged; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism; D001327:Autoimmune Diseases / Q000175:diagnosis / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology*; D001706:Biopsy; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D005260:Female; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008875:Middle Aged; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D015398:Signal Transduction; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D019408:Platelet Endothelial Cell Adhesion Molecule-1; D051746:ZAP-70 Protein-Tyrosine Kinase; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
keywords: Autoimmune arthritis; CD31; ITIM; Immunological synapse; Inhibitory receptors; T lymphocytes