Genetic Deficiency of Itgb2 or ItgaL Prevents Autoimmune Diabetes Through Distinctly Different Mechanisms in NOD/LtJ Mice

Genetic Deficiency of Itgb2 or ItgaL Prevents Autoimmune Diabetes Through Distinctly Different Mechanisms in NOD/LtJ Mice John D. Glawe 1 , D. Ross Patrick 1 , Meng Huang 1 , Christopher D. Sharp 1 , Shayne C. Barlow 2 and Christopher G. Kevil 1 1 Department of Pathology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana; 2 Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina. Corresponding author: Christopher Kevil, ckevil{at}lsuhsc.edu . Abstract OBJECTIVE Insulitis is an important pathological feature of autoimmune diabetes; however, mechanisms governing the recruitment of diabetogenic T-cells into pancreatic islets are poorly understood. Here, we determined the importance of leukocyte integrins β 2 (Itgb2) and αL (ItgaL) in developing insulitis and frank diabetes. RESEARCH DESIGN AND METHODS Gene-targeted mutations of either Itgb2 or ItgaL were established on the NOD/LtJ mouse strain. Experiments were performed to measure insulitis and diabetes development. Studies were also performed measuring mutant T-cell adhesion to islet microvascular endothelial cells under hydrodynamic flow conditions. T-cell adhesion molecule profiles and adoptive transfer studies were also performed. RESULTS Genetic deficiency of either Itgb2 or ItgaL completely prevented the development of hyperglycemia and frank diabetes in NOD mice. Loss of Itgb2 or ItgaL prevented insulitis with Itgb2 deficiency conferring complete protection. In vitro hydrodynamic flow adhesion studies also showed that loss of Itgb2 completely abrogated T-cell adhesion. However, ItgaL deficiency did not alter NOD T-cell adhesion to or transmigration across islet endothelial cells. Adoptive transfer of ItgaL-deficient splenocytes into NOD/Rag-1 mice did not result in development of diabetes, suggesting a role for ItgaL in NOD/LtJ T-cell activation. CONCLUSIONS Together, these data demonstrate that genetic deficiency of Itgb2 or ItgaL confers protection against autoimmune diabetes through distinctly different mechanisms. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. See accompanying commentary, p. 1257 . . Received June 17, 2008. Accepted February 11, 2009. Readers may use this article as long as the work is