title: CD31 signals confer immune privilege to the vascular endothelium.
abstract: Constitutive resistance to cell death induced by inflammatory stimuli activating the extrinsic pathway of apoptosis is a key feature of vascular endothelial cells (ECs). Although this property is central to the maintenance of the endothelial barrier during inflammation, the molecular mechanisms of EC protection from cell-extrinsic, proapoptotic stimuli have not been investigated. We show that the Ig-family member CD31, which is expressed by endothelial but not epithelial cells, is necessary to prevent EC death induced by TNF-α and cytotoxic T lymphocytes in vitro. Combined quantitative RT-PCR array and biochemical analysis show that, upon the engagement of the TNF receptor with TNF-α on ECs, CD31 becomes activated and, in turn, counteracts the proapoptotic transcriptional program induced by TNF-α via activation of the Erk/Akt pathway. Specifically, Akt activation by CD31 signals prevents the localization of the forkhead transcription factor FoxO3 to the nucleus, thus inhibiting transcription of the proapoptotic genes CD95/Fas and caspase 7 and de-repressing the expression of the antiapoptotic gene cFlar. Both CD31 intracellular immunoreceptor tyrosine-based inhibition motifs are required for its prosurvival function. In vivo, CD31 gene transfer is sufficient to recapitulate the cytoprotective mechanisms in CD31(-) pancreatic β cells, which become resistant to immune-mediated rejection when grafted in fully allogeneic recipients.
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: Kenneth
authors.initials: K
authors.lastname: Cheung
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: Guosu
authors.initials: G
authors.lastname: Wang
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: David
authors.initials: D
authors.lastname: Coe
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ferro
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute Biosciences, Curtin University, Perth, Western Australia 6102, Australia;
authors.forename: Marco
authors.initials: M
authors.lastname: Falasca
authors.affiliation: Medical Research Centre Centre for Immune Regulation, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: Claudio
authors.initials: C
authors.lastname: Mauro
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom; f.marelli-berg@qmul.ac.uk.
authors.forename: Federica M
authors.initials: FM
authors.lastname: Marelli-Berg
mesh_terms: D000818:Animals; D004730:Endothelium, Vascular / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D019408:Platelet Endothelial Cell Adhesion Molecule-1; D014409:Tumor Necrosis Factor-alpha
keywords: endothelium; immunology; inflammation; lymphocytes; transplantation