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 tyrosinebased 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.endothelium | immunology | inflammation | lymphocytes | transplantation

Soothing touch of CD31 protects endothelium during cellular immune responses

“…1A). In line with this hypothesis, the authors showed that CD31 gene transfer was sufficient to recapitulate the cytoprotective mechanisms in CD31-negative pancreatic beta cells, which became resistant to T-cell-mediated rejection when grafted in fully allogeneic recipients (2).…”

“…Akt activation by CD31 signaling in endothelial cells prevented the localization of the forkhead transcription factor FoxO3 to the nucleus, thus inhibiting the transcription of the proapoptotic genes and derepressing expression of the antiapoptotic gene cFlar (2). This study therefore provides important novel insights on the molecular mechanisms whereby the vascular endothelium remains undamaged while interacting with effector immune cells migrating to the site of the response.…”

“…Chronic vascular inflammation promotes the development of typical histological lesions and irreversible loss of graft function (11,12). Interestingly, Cheung et al (2) show in their study that CD31-mediated cytoprotection did not extend to mechanisms of cell death other than apoptosis: CD31 KO and CD31 WT endothelial cells were equally sensitive to antibody-mediated cell death.…”

“…These catalytic enzymes, once localized to their cytoplasmic anchors and activated, are then able to inhibit tyrosine kinase-mediated signaling, and thus cellular activation (1). Building on these data, Cheung et al (2) present in PNAS another advance in the understanding of the regulatory roles of CD31. Their study demonstrates that CD31 signaling through ITIM is necessary to prevent inflammatory-induced endothelial cell death.…”

“…Combining different approaches, Cheung et al (2) demonstrate that exposure of endothelial cells to various inflammatory stimuli in vitro, including TNFα and cytotoxic T lymphocytes, resulted in the phosphorylation of the ITIMs of CD31, which counteracted the activation of the extrinsic pathway of apoptosis via the activation of the Erk/Akt pathway. Akt activation by CD31 signaling in endothelial cells prevented the localization of the forkhead transcription factor FoxO3 to the nucleus, thus inhibiting the transcription of the proapoptotic genes and derepressing expression of the antiapoptotic gene cFlar (2).…”