SDF-1/CXCL12 stimulates chemorepulsion of NOD/LtJ T cell adhesion to islet microvascular endothelium

Abstract

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 polymorphisms of SDF-1 are associated with early development of T1D.

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 TNFα, 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: TNFα 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 TNFα activated islet endothelium demonstrating that SDF-1 augments normal T cell adhesion. SDF-1 chemorepulsion of NOD/LtJ T cell adhesion was completely reversed by blocking G_iα-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 NOD/LtJ diabetogenic T cell adhesion which may be important in regulating diabetogenic T cell recruitment into islets.