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Human DQ8 Can Substitute for Murine I-A^g7 in the Selection of Diabetogenic T Cells Restricted to I-A^g71

Li Wen^2,*, F. Susan Wong, Robert Sherwin^* and Conchi Mora

^* Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520; Department of Pathology and Microbiology, University of Bristol, Bristol, United Kingdom; and Laboratori Experimental de Diabetis, Hospital Clinic Universitari, Barcelona, Spain

The strong association of type 1 diabetes with specific MHC class II genes, such as I-A^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 I-A^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 I-A^g7, but also can cross the species barrier and functionally replace I-A^g7 molecules to stimulate diabetogenic T cells and produce diabetes.

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