CD31 signals confer immune privilege to the vascular endothelium

Kenneth Chat Pan Cheung, Liang Ma, Guosu Wang, David Coe, Riccardo Ferro, Marco Falasca, Christopher D Buckley, Claudio Mauro, Federica M Marelli-Berg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)E5815-5824
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number43
DOIs
Publication statusPublished - 27 Oct 2015
Externally publishedYes

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