Molecular mechanisms of endothelial cytoprotection by CD31-mediated signals
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Maintenance of vascular integrity during inflammation is a major challenge for the cooperation between the immune and the vascular systems. Continuous exposure to inflammatory stimuli is a risk for dysfunction of the vascular endothelial cells. The objectives of this study were to assess 1) the cytoprotective role of CD31 to TNFα and cytotoxic T lymphocytes in both in vitro and in vivo allotransplantation settings and 2) the role of CD31 in the regulation of T cell: EC interactions during leukocyte extravasation in response to inflammatory stimuli. My results first showed that the Ig-family member CD31, which is expressed by endothelial but not epithelial cells, is necessary to prevent primary EC death induced by TNFα and cytotoxic T lymphocytes in vitro. Combined qRT-PCR array and biochemical analysis showed that, upon engagement of TNF-R with TNFα on ECs, CD31 becomes activated and, in turn, modulates the pro-apoptotic transcriptional programme induced by TNFα via activation of Erk and Akt pathways. Specifically, Akt activation by CD31 signals prevents the localization of the forkhead transcription factor FoxO3 to the nucleus, thus inhibiting transcription of the pro-apoptotic genes CD95/Fas and Caspase 7 and de-repressing expression of the anti-apoptotic gene cFlar. Both CD31 intracellular ITIM motifs are required for its pro-survival function. Importantly, CD31 gene transfer is sufficient to recapitulate the cytoprotective mechanisms in CD31-negative pancreatic beta cells, which become resistant to immune-mediated rejection when grafted in fully allogeneic recipients. Secondly, using CD31-deficient mice, I show that CD31 regulates both constitutive and inflammation-induced T cell migration in vivo. Specifically, T cell:EC interactions mediated by CD31 molecules are required for efficient localization of naive T lymphocytes to secondary lymphoid tissue and constitutive recirculation of primed T cells to nonlymphoid tissues. In inflammatory conditions, T cell:EC CD31-mediated interactions facilitate T cell recruitment to Ag-rich sites. However, endothelial CD31 also provides a gate-keeping mechanism to limit the rate of Ag-driven T cell extravasation. This event contributes to the formation of Ag-specific effector T cell infiltrates and is induced by recognition of Ag on the endothelium. In this context, CD31 engagement is required for restoring endothelial continuity, which is temporarily lost upon MHC molecule ligation by migrating cognate T cells. I propose that integrated adhesive and signaling functions of CD31 molecules exert a complex regulation of T cell trafficking, a process that is differentially adapted depending on cell-specific expression, the presence of inflammatory conditions and the molecular mechanism facilitating T cell extravasation.
AuthorsCheung, Chat Pan Kenneth
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