New T Cell Coinhibitory Pathway and Type 1 Diabetes

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Immunology T lymphocytes are central mediators of adaptive immunity, playing a key role in both appropriate immune responses (such as immunity against pathogens) and abnormal ones (such as autoimmune response that lead to type 1 diabetes). Optimal activation, proliferation, and differentiation to effector function of T cells require a simultaneous occurrence of two signals: antigen specific signals via T cell antigen receptors, and additional costimulatory signals (costimulation) generated mainly by the interaction between the B7 and CD28 families. The intense effort towards understanding T cell costimulation of B7-1, B7-2/CD28, CTLA-4 pathway over the past decade has shaped much of our understanding regarding the immune system and immune-related diseases such as type 1 diabetes. We have discovered the newest member of the B7 family, B7x, which is capable of inhibiting T cell function in vitro (coinhibition). However, the role of B7x in diabetes is unknown. Interestingly, we have recently found that, unlike B7-1 and B7-2, both human and mouse B7x genes are located in insulin- dependent diabetes loci and are expressed in pancreatic islets. Moreover, we have found that transgenic mice overexpressing B7x in pancreatic ¿ cells are resistant to CD4 T cell mediated type 1 diabetes. Based on the preliminary data, we have hypothesized that B7x represents a novel T cell coinhibitory pathway that attenuates effector T cell function in pancreas. We have generated a number of important tools (mAbs to B7x, B7x transgenic mice, B7x knock-out mice, etc.) that provide us with unique opportunities to analyze the role of B7x pathway in type 1 diabetes. Overall, the studies of this project may not only advance our understanding of the pathogenic processes underlying type 1 diabetes and its complicatios but also lead to a rational approach for clinical therapeutic intervention.