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[摘要]：OBJECTIVE-Diabetogenic T-cell recruitment into pancreatic islets faciltates beta-cell destruction during autoimmune diabetes, yet specific mechanisms governing this process are poorly understood. The chemokine stromal cell-derived factor-1 (SDF-1) controls T-cell recruitment, and genetic polymorpliisms of SDF-1 are associated with early development of type 1 diabetes.RESEARCH DESIGN AND METHODS-Here, we examined the role of SDF-1 regulation of diabetogenic T-cell adhesion to islet microvascular endothelium. Islet microvascular endothelial cell monolayers were activated with tumor necrosis factor-alpha (TNF-alpha), subsequently coated with varying concentrations of SDF-1 (1-100 ng/ml), and assayed for T-cell/endothelial cell interactions under physiological flow conditions.RESULTS-TNF-alpha. significantly increased NOD/LtJ T-cell adhesion, which was completely blocked by SDF-1 in a dose-dependent manner, revealing a novel chemorepulsive effect. Conversely, SDF-1 enhanced C57BL/6J T-cell adhesion to TNF-alpha-activated islet endothelium, demonstrating that SDF-1 augments normal T-cell adhesion. SDF-1 chemorepulsion of NOW LtJ T-cell adhesion was completely reversed by blocking G(i)alpha-protein-coupled receptor activity with pertussis toxin. CXCR4 protein expression was significantly decreased in NOD/LtJ T-cells, and inhibition of CXCR4 activity significantly reversed SDF-1 chemorepulsive effects. Interestingly, SDF-1 treatment significantly abolished T-cell resistance to shear-mediated detachment without altering adhesion molecule expression, thus demonstrating decreased integrin affinity and avidity.CONCLUSIONS-In this study, we have identified a previously unknown novel function of SDF-1 in negatively regulating NOW LtJ diabetogenic T-cell adhesion, which may be important in regulating diabetogenic T-cell recruitment into islets. |
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