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SDF-1-CXCR4 differentially regulates autoimmune diabetogenic T cell adhesion through ROBO1-SLIT2 interactions in mice.
Diabetologia. 2013 Oct; 56(10):2222-30.D

Abstract

AIMS/HYPOTHESIS

We had previously reported that stromal cell-derived factor 1 (SDF-1) mediates chemorepulsion of diabetogenic T cell adhesion to islet microvascular endothelium through unknown mechanisms in NOD mice. Here we report that SDF-1-mediated chemorepulsion occurs through slit homologue (SLIT)2-roundabout, axon guidance receptor, homologue 1 (Drosophila) (ROBO1) interactions.

METHODS

C-X-C receptor (CXCR)4 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 SDF-1-mediated T cell chemorepulsion. Diabetogenic splenocyte transfer was performed in NOD/LtSz Rag1(-/-) mice to examine the effect of the SDF-1 mimetic CTCE-0214 on adoptive transfer of diabetes.

RESULTS

CXCR4 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 SDF-1-mediated chemorepulsion of NOD T cell firm adhesion to TNFα-stimulated islet endothelial cells. SDF-1 increased NOD T cell adhesion to recombinant adhesion molecules, a phenomenon that was reversed by recombinant SLIT2. Finally, we found that an SDF-1 peptide mimetic prevented NOD T cell adhesion in vitro and significantly delayed adoptive transfer of autoimmune diabetes in vivo.

CONCLUSIONS/INTERPRETATION

These data reveal a novel molecular pathway, which regulates diabetogenic T cell recruitment and may be useful in modulating autoimmune diabetes.

Authors+Show Affiliations

Department of Pathology, LSU Health-Shreveport, 1501 Kings Highway, Shreveport, LA 71130, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23811810

Citation

Glawe, John D., et al. "SDF-1-CXCR4 Differentially Regulates Autoimmune Diabetogenic T Cell Adhesion Through ROBO1-SLIT2 Interactions in Mice." Diabetologia, vol. 56, no. 10, 2013, pp. 2222-30.
Glawe JD, Mijalis EM, Davis WC, et al. SDF-1-CXCR4 differentially regulates autoimmune diabetogenic T cell adhesion through ROBO1-SLIT2 interactions in mice. Diabetologia. 2013;56(10):2222-30.
Glawe, J. D., Mijalis, E. M., Davis, W. C., Barlow, S. C., Gungor, N., McVie, R., & Kevil, C. G. (2013). SDF-1-CXCR4 differentially regulates autoimmune diabetogenic T cell adhesion through ROBO1-SLIT2 interactions in mice. Diabetologia, 56(10), 2222-30. https://doi.org/10.1007/s00125-013-2978-x
Glawe JD, et al. SDF-1-CXCR4 Differentially Regulates Autoimmune Diabetogenic T Cell Adhesion Through ROBO1-SLIT2 Interactions in Mice. Diabetologia. 2013;56(10):2222-30. PubMed PMID: 23811810.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SDF-1-CXCR4 differentially regulates autoimmune diabetogenic T cell adhesion through ROBO1-SLIT2 interactions in mice. AU - Glawe,John D, AU - Mijalis,Eleni M, AU - Davis,William C, AU - Barlow,Shayne C, AU - Gungor,Neslihan, AU - McVie,Robert, AU - Kevil,Christopher G, Y1 - 2013/06/28/ PY - 2013/03/15/received PY - 2013/06/07/accepted PY - 2013/7/2/entrez PY - 2013/7/3/pubmed PY - 2014/4/12/medline SP - 2222 EP - 30 JF - Diabetologia JO - Diabetologia VL - 56 IS - 10 N2 - AIMS/HYPOTHESIS: We had previously reported that stromal cell-derived factor 1 (SDF-1) mediates chemorepulsion of diabetogenic T cell adhesion to islet microvascular endothelium through unknown mechanisms in NOD mice. Here we report that SDF-1-mediated chemorepulsion occurs through slit homologue (SLIT)2-roundabout, axon guidance receptor, homologue 1 (Drosophila) (ROBO1) interactions. METHODS: C-X-C receptor (CXCR)4 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 SDF-1-mediated T cell chemorepulsion. Diabetogenic splenocyte transfer was performed in NOD/LtSz Rag1(-/-) mice to examine the effect of the SDF-1 mimetic CTCE-0214 on adoptive transfer of diabetes. RESULTS: CXCR4 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 SDF-1-mediated chemorepulsion of NOD T cell firm adhesion to TNFα-stimulated islet endothelial cells. SDF-1 increased NOD T cell adhesion to recombinant adhesion molecules, a phenomenon that was reversed by recombinant SLIT2. Finally, we found that an SDF-1 peptide mimetic prevented NOD T cell adhesion in vitro and significantly delayed adoptive transfer of autoimmune diabetes in vivo. CONCLUSIONS/INTERPRETATION: These data reveal a novel molecular pathway, which regulates diabetogenic T cell recruitment and may be useful in modulating autoimmune diabetes. SN - 1432-0428 UR - https://www.unboundmedicine.com/medline/citation/23811810/SDF_1_CXCR4_differentially_regulates_autoimmune_diabetogenic_T_cell_adhesion_through_ROBO1_SLIT2_interactions_in_mice_ L2 - https://doi.org/10.1007/s00125-013-2978-x DB - PRIME DP - Unbound Medicine ER -