University of California, San Francisco (UCSF)

Role of Thymic Antigen Presentation in Selection of Diabetogenic T Cells

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The ability of the immune system to defend against pathogens requires a system of checks and balances to prevent attack on self-tissues, a process known as immune tolerance. Breakdown of immune tolerance results in autoimmune diseases, like type 1 diabetes (T1D), in which T cells specific for beta cell antigens become abnormally activated and initiate an immune attack on the islets. T cells develop in the thymus where they are educated by a specialized subset of cells, called medullary thymic epithelial cells (mTECs). mTECs express a library of self-antigens that are normally present only in peripheral organs. When self-reactive T cells interact with self-antigen presented by mTECs, they either die or become regulatory T cells. My project examines how presentation of self-antigens by mTECs shapes the development of self-reactive T cells. Our lab has developed a novel mouse model which allows for ablation of antigen-presenting function specifically on mTECs, leading to escape of self-reactive T cells. This model allows medissect the contribution of mTECs to the selection of diabetogenic T cells and the ability of escaped T cells to promote disease. In addition, I am using a singe-cell RNA sequencing approach to identify T-cell receptors that escape tolerance in this setting. In this way, I hope to determine the mechanisms and critical T cell specificities that initiate the autoimmune response, which in turn can then provide more specific targets for future interventions in restoring immune tolerance in diabetes.