Genetic deficiency of Itgb2 or ItgaL prevents autoimmune diabetes through distinctly different mechanisms in NOD/LtJ mice

Abstract

Significance: 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 determine the importance of leukocyte integrins Itgb2 and ItgaL in developing insulitis and frank diabetes.

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 done 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 of 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 confer protection against autoimmune diabetes through distinctly different mechanisms.