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Endothelial Cell Activation and Proliferation Modulate NKG2D Activity by Regulating MICA Expression and Shedding

Abstract : MICA are major histocompatibility complex class I-related molecules, expressed by endothelial cells (ECs), that may be targets for alloantibodies and NKG2D-expressing natural killer (NK) and T effector cells in organ allografts. This study shows that basal levels of MICA expressed on vascular ECs is sufficient to functionally modulate the expression and activity of the immunoreceptor NKG2D in allogeneic NK cells. We found that MICA expression is differentially regulated at the EC surface in response to cytokines. TNFα upregulates MICA while IFNγ significantly decreases MICA at the EC surface. Both cytokines induce the release of soluble MICA by ECs. Modulation of NKG2D correlates with the MICA level on the EC surface. Glycosylation and metalloproteinase activities account for major post-transcriptional mechanisms controlling MICA level and the function in ECs. Our results indicate that, in addition to the NFκB pathway, the mitogen-activated protein kinase pathways JNK, ERK1/2 and p38 are key signaling pathways in the control of MICA by the cytokines. Finally, we show that EC proliferation mediated by FGF-2 or wound healing increases the MICA level. Together, our data suggest that inflammation and proliferation regulate endothelial MICA expression and shedding, enabling ECs to modulate NKG2D activity on effector NK and T cells, and provide further evidence of a role for ECs in immunoregulation.
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Submitted on : Monday, June 24, 2019 - 11:54:38 AM
Last modification on : Wednesday, April 27, 2022 - 3:59:08 AM

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Annabelle Chauveau, Pierre Tonnerre, Angélique Pabois, Pierre Gavlovsky, Mathais Chatelais, et al.. Endothelial Cell Activation and Proliferation Modulate NKG2D Activity by Regulating MICA Expression and Shedding. Journal of Innate Immunity, Karger, 2014, 6 (1), pp.89-104. ⟨10.1159/000351605⟩. ⟨inserm-02163395⟩



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