Authors: John D Glawe Eleni M Mijalis William C Davis Shayne C Barlow Neslihan Gungor Robert McVie Christopher G Kevil
Publish Date: 2013/06/28
Volume: 56, Issue: 10, Pages: 2222-2230
Abstract
We had previously reported that stromal cellderived factor 1 SDF1 mediates chemorepulsion of diabetogenic T cell adhesion to islet microvascular endothelium through unknown mechanisms in NOD mice Here we report that SDF1mediated chemorepulsion occurs through slit homologue SLIT2roundabout axon guidance receptor homologue 1 Drosophila ROBO1 interactionsCXC receptor CXCR4 and ROBO1 protein expression was measured in mouse and human T cells Parallel plate flow chamber adhesion and detachment studies were performed to examine the molecular importance of ROBO1 and SLIT2 for SDF1mediated T cell chemorepulsion Diabetogenic splenocyte transfer was performed in NOD/LtSz Rag1 −/− mice to examine the effect of the SDF1 mimetic CTCE0214 on adoptive transfer of diabetesCXCR4 and ROBO1 protein expression was elevated in diabetic NOD/ShiLtJ T cells over time and coincided with the onset of hyperglycaemia CXCR4 and ROBO1 expression was also increased in human type 1 diabetic T cells with ROBO1 expression maximal at less than 1 year post diagnosis Cell detachment studies revealed that immunoneutralisation of ROBO1 prevented SDF1mediated chemorepulsion of NOD T cell firm adhesion to TNFαstimulated islet endothelial cells SDF1 increased NOD T cell adhesion to recombinant adhesion molecules a phenomenon that was reversed by recombinant SLIT2 Finally we found that an SDF1 peptide mimetic prevented NOD T cell adhesion in vitro and significantly delayed adoptive transfer of autoimmune diabetes in vivo
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