CD31 signals confer immune privilege to the vascular endothelium
2015
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,
CD31becomes activated and, in turn, counteracts the proapoptotic transcriptional program induced by TNF-α via activation of the Erk/Akt pathway. Specifically, Akt activation by
CD31signals prevents the localization of the forkhead transcription factor
FoxO3to the nucleus, thus inhibiting transcription of the proapoptotic genes CD95/Fas and
caspase 7and de-repressing the expression of the antiapoptotic gene
cFlar. Both
CD31intracellular immunoreceptor tyrosine-based inhibition motifs are required for its prosurvival function. In vivo,
CD31gene transfer is sufficient to recapitulate the
cytoprotectivemechanisms in
CD31− pancreatic β cells, which become resistant to immune-mediated rejection when grafted in fully allogeneic recipients.
Keywords:
-
Correction
-
Source
-
Cite
-
Save
54
References
38
Citations
NaN
KQI