The strong association of type 1 diabetes with specific MHC class II genes, such as IA g7 in nonobese diabetic mice and HLA-DQ8 in humans, suggests that MHC class II molecules play an important role in the development of the disease. To test whether human DQ8 molecules could cross the species barrier and functionally replace their murine homolog IA g7, we generated DQ8/BDC2. 5 transgenic mice. We have shown that BDC2. 5 transgenic T cells are selected on DQ8 in the thymus and cause diabetes in a manner similar to that seen when the T cells are selected on H2 g7. Splenocytes from DQ8/BDC2. 5 mice also showed reactivity toward islets in vitro as seen in H-2 g7/BDC2. 5 mice. We conclude that DQ8 molecules not only share structural similarity with the murine homolog IA g7, but also can cross the species barrier and functionally replace IA g7 molecules to stimulate diabetogenic T cells and produce diabetes.