In vivo evidence for the contribution of human histocompatibility leukocyte antigen (HLA)-DQ molecules to the development of diabetes

Although DQA1*0301/DQB1*0302 is the human histocompatibility leukocyte antigen (HLA) class II gene most commonly associated with human type I diabetes, direct in vivo experimental evidence for its diabetogenic role is lacking. Therefore, we generated C57BL/6 transgenic mice that bear this molecule and do not express mouse major histocompatibility complex (MHC) class II molecules (DQ8⁺/mII^-). They did not develop insulitis or spontaneous diabetes. However, when DQ8⁺/mII^- mice were bred with C57BL/6 mice expressing costimulatory molecule B7-1 on β cells (which normally do not develop diabetes), 81% of the DQ8⁺/mII^-/B7-1⁺ mice developed spontaneous diabetes. The diabetes was accompanied by severe insulitis composed of both T cells (CD4⁺ and CD8⁺) and B cells. T cells from the diabetic mice secreted large amounts of interferon γ, but not interleukin 4, in response to DQ8⁺ islets and the putative islet autoantigens, insulin and glutamic acid decarboxylase (GAD). Diabetes could also be adoptively transferred to irradiated nondiabetic DQ8⁺/mII^-/B7-1⁺ mice. In striking contrast, none of the transgenic mice in which the diabetes protective allele (DQA1*0103/DQB1*0601, DQ6 for short) was substituted for mouse MHC class II molecules but remained for the expression of B7-1 on pancreatic β cells (DQ6⁺/mII-/B7-1⁺) developed diabetes. Only 7% of DQ-/mII-/B7-1⁺ mice developed diabetes at an older age, and none of the DQ-/mII+/B7-1⁺ mice or DQ8⁺/mII+/B7-1⁺ mice developed diabetes. In conclusion, substitution of HLA-DQA1*0301/DQB1*0302, but not HLA-DQA1*0103/DQB1*0601, for murine MHC class II provokes autoimmune diabetes in non-diabetes-prone rat insulin promoter (RIP).B7-1 C57BL/6 mice. Our data provide direct in vivo evidence for the diabetogenic effect of this human MHC class II molecule and a unique 'humanized' animal model of spontaneous diabetes.