Stromal cell-derived factor-1/CXCL12 stimulates chemorepulsion of NOD/LtJ T-cell adhesion to islet microvascular endothelium.
OBJECTIVE
Diabetogenic T-cell recruitment into pancreatic islets facilitates 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 type 1 diabetes.


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 NOD/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 NOD/LtJ diabetogenic T-cell adhesion, which may be important in regulating diabetogenic T-cell recruitment into islets.
Sharp
Christopher D
CD
Department of Pathology, Louisiana State University Health Sciences Center-Shreveport, 1501 Kings Hwy., Shreveport, LA 71130-3932, USA.
Huang
Meng
M
Glawe
John
J
Patrick
D Ross
DR
Pardue
Sible
S
Barlow
Shayne C
SC
Kevil
Christopher G
CG
D000818:Animals; D017252:CD3 Complex / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D004730:Endothelium, Vascular; D005260:Female; D005434:Flow Cytometry; D007515:Islets of Langerhans / Q000276:immunology* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008833:Microcirculation; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000502:physiology; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D017252:CD3 Complex; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4