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Diabetes Publish Ahead of Print published online ahead of print October 1, 2007
DOI: 10.2337/db07-0494
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Original Research

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

Christopher D. Sharp1, Meng Huang1, John Glawe1, D. Ross Patrick1, Sible Pardue1, Shayne C. Barlow2, and Christopher G. Kevil1

1Department of Pathology, LSU Health Sciences Center-Shreveport
2Department of Pharmacology, Physiology and Neuroscience, University of South Carolina, Columbia, SC

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 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 NOD/LtJ T cell adhesion was completely reversed by blocking Gi{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 NOD/LtJ diabetogenic T cell adhesion which may be important in regulating diabetogenic T cell recruitment into islets.

Correspondence: ckevil{at}lsuhsc.edu

Key Words: chemokines • autoimmune diabetes • T cell adhesion • endothelial cell


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