期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：43
页码：E5815-E5824
DOI：10.1073/pnas.1509627112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceMaintenance of vascular integrity during effector immune responses occurring in tissues is a prerequisite of a healthy immune response. The mechanism whereby the vascular endothelium remains undamaged while interacting with effector immune cells migrating to the site of inflammation is largely unknown. This study shows that signals mediated by CD31, a trans-homophilic receptor expressed at high levels by the endothelium, are both necessary and sufficient to prevent inflammation-induced endothelial cell death and confer immune privilege to the vascular endothelium. We also provide proof of principle that this property can be harnessed therapeutically in pancreatic {beta}-cell transplantation, whereby CD31 gene transfer alone endows allogeneic targets with indefinite resistance to immune attack in vivo. 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- 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- on ECs, CD31 becomes activated and, in turn, counteracts the proapoptotic transcriptional program induced by TNF- 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 {beta} cells, which become resistant to immune-mediated rejection when grafted in fully allogeneic recipients.
