Genetic deficiency of Itgb2 or ItgaL prevents autoimmune diabetes through distinctly different mechanisms in NOD/LtJ mice.
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 beta(2)(Itgb2) and alphaL (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 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.
Glawe
John D
JD
Department of Pathology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, USA.
Patrick
D Ross
DR
Huang
Meng
M
Sharp
Christopher D
CD
Barlow
Shayne C
SC
Kevil
Christopher G
CG
D000818:Animals; D040881:CD11a Antigen / Q000235:genetics*; D018821:CD18 Antigens / Q000235:genetics*; D017252:CD3 Complex / Q000276:immunology; D002448:Cell Adhesion; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D005434:Flow Cytometry; D007003:Hypoglycemia / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009154:Mutation; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D040881:CD11a Antigen; D018821:CD18 Antigens; D017252:CD3 Complex