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

Christopher Sharp, Meng Huang, John Glawe, D. Ross Patrick, Sible Pardue, Shayne C. Barlow, Christopher G. Kevil

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE - Diabetogenic T-cell recruitment into pancreatic islets faciltates β-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 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-α (TNF-α), 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-α 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-α-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 Giα-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.

Original languageEnglish (US)
Pages (from-to)102-112
Number of pages11
JournalDiabetes
Volume57
Issue number1
DOIs
StatePublished - Jan 1 2008

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Chemokine CXCL12
Cell Adhesion
Endothelium
T-Lymphocytes
Tumor Necrosis Factor-alpha
Type 1 Diabetes Mellitus
Islets of Langerhans
Endothelial Cells
Pertussis Toxin
Genetic Polymorphisms
Chemokines
Integrins
Cell Communication
Proteins
Research Design

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Sharp, C., Huang, M., Glawe, J., Patrick, D. R., Pardue, S., Barlow, S. C., & Kevil, C. G. (2008). Stromal cell-derived factor-1/CXCL12 stimulates chemorepulsion of NOD/LtJ T-cell adhesion to islet microvascular endothelium. Diabetes, 57(1), 102-112. https://doi.org/10.2337/db07-0494

Stromal cell-derived factor-1/CXCL12 stimulates chemorepulsion of NOD/LtJ T-cell adhesion to islet microvascular endothelium. / Sharp, Christopher; Huang, Meng; Glawe, John; Patrick, D. Ross; Pardue, Sible; Barlow, Shayne C.; Kevil, Christopher G.

In: Diabetes, Vol. 57, No. 1, 01.01.2008, p. 102-112.

Research output: Contribution to journalArticle

Sharp, C, Huang, M, Glawe, J, Patrick, DR, Pardue, S, Barlow, SC & Kevil, CG 2008, 'Stromal cell-derived factor-1/CXCL12 stimulates chemorepulsion of NOD/LtJ T-cell adhesion to islet microvascular endothelium', Diabetes, vol. 57, no. 1, pp. 102-112. https://doi.org/10.2337/db07-0494
Sharp, Christopher ; Huang, Meng ; Glawe, John ; Patrick, D. Ross ; Pardue, Sible ; Barlow, Shayne C. ; Kevil, Christopher G. / Stromal cell-derived factor-1/CXCL12 stimulates chemorepulsion of NOD/LtJ T-cell adhesion to islet microvascular endothelium. In: Diabetes. 2008 ; Vol. 57, No. 1. pp. 102-112.
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AU - Kevil, Christopher G.

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AB - OBJECTIVE - Diabetogenic T-cell recruitment into pancreatic islets faciltates β-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 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-α (TNF-α), 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-α 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-α-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 Giα-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.

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