University of California, San Francisco (UCSF)

The Role of Aire in the Selection of Diabetogenic T Cells

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Our work aims to understand the mechanisms by which autoreactive T cells escape mechanisms of central tolerance in type 1 diabetes. As T cells mature, negative selection purges self-reactive cells from the repertoire. This process involves autoimmune regulator (Aire), which promotes the expression of peripheral self-antigens within specialized thymic stromal cells. Accordingly, Aire-deficient mice exhibit a breakdown in tolerance characterized by hyperactive T cells and autoimmunity in multiple organs including the pancreas.

Because insulin peptide is a major autoantigen detected by pathogenic T cells, and Aire controls insulin expression in the thymus, we hypothesize that Aire is important for the deletion of insulin-specific T cells. Thus, we are using novel transgenic mouse models that express insulin-specific TCRs to dissect the importance of Aire and thymic insulin in the deletion of diabetogenic T cells. Previous studies determined that T cell clones isolated from pancreatic islets of NOD mice recognize residues 9-23 of the insulin beta chain, which can be presented by the MHC class II molecule I-Ag7 in multiple positions or registers with varying affinity. Furthermore, data suggests that antigen processing and presentation in the pancreas may generate unique insulin peptides not presented in the thymus. We are determining if Aire promotes the expression of specific MHC class II binding registers in the thymus, and, conversely, if diabetogenic T cells that escape deletion recognize registers uniquely presented in the periphery. Ultimately, information gained from these studies could be valuable towards developing methods that establish tolerance in humans with increased risk for type 1 diabetes.