T cell receptor (TCR) dictates T cell fate decision during development, steady state/homeostasis, and antigenic stimulation in periphery. Recent expansion of deep sequencing technologies has uncovered a previously underappreciated TCR diversity within antigen specific T cell responses. TCR diversity suggests a potential for functionally diverse T cell response where TCR parameters command T cell fate decisions: T helper lineage development, T cell activation, or T cell development into a regulatory T cell lineage. In order to understand the implications of this diversity observed in TCR repertoire studies, we need to combine such approaches with functional analysis of TCRs. We are proposing to utilize a combination of technologically advanced approaches to dissect TCR parameters that control Foxp3+ T cell development and function in autoimmunity. Development of type 1 diabetes is driven primarily by self-reactive T cells, which specifically recognize and target insulin producing beta cells for destruction. We have previously published that beta cell reactive TCRs vary in their ability to induce accumulation of T regulatory cells (Tregs) in the pancreatic islets of mice. Multiple studies suggest that the strength of the TCR signal leading to Treg selection, expansion, and survival is unique and distinct from T effector T cells. However, functional implications of a unique Treg TCR repertoire, such as antigenic specificity, Treg accumulation, function, and stability of their regulatory phenotype in autoimmune diabetes are largely unknown. We hypothesize that distinct TCR repertoire of islet infiltrating Tregs has intrinsic functional differences. The proposed study will systematically characterize TCR repertoire, function, and signaling characteristic of islet infiltrating Treg TCRs. We will use TCR retrogenic approach in combination with cutting edge genetic mouse models to test the function of insulin reactive Treg TCRs in single TCR and competitive environments in the presence or absence of insulin epitope. The ultimate goal of this proposal is to uncover functional implications of Treg specific TCR parameters in autoimmunity. Insights gained from this study may lead to a significant impact on our understanding of the mechanisms behind Treg function and failure in autoimmunity, and reveal potential avenues to improve development or homeostasis of Tregs with relevant antigenic specificities.
The proposed study will identify functional implications of the unique T cell receptor repertoire associated with T regulatory cells in type 1 diabetes. The knowledge gained from this application may lead to a significant impact on our understanding of autoimmunity, and reveal potential avenues to improve development or homeostasis of regulatory T cells for treatment of autoimmune disease.
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