While the development of powerful immunosuppressive medications enabled the use of organ transplantation as a treatment for end-stage organ failure, current immunosuppression protocols drive many co-morbidities; thus, they now present a critical limitation to long-term health and quality of life for transplant recipients. Replacing conventional immunosuppression with treatments to induce donor-specific immune tolerance would eliminate life-long exposure to drug toxicity and high risk of severe infections and malignancies for transplant recipients. Therefore, a large amount of research has been devoted to developing therapies to induce donor-specific immune tolerance. While there are treatments that induce permanent allograft acceptance in animal models and there are limited reports of immunosuppression-free graft survival in patients, tolerance observed in these circumstances is vulnerable to inflammatory challenges. To become a standard of care for transplant recipients, donor-specific tolerance must induce stable graft survival that resists bouts of inflammation. In this dissertation, we study the mechanisms maintaining tolerance long-term in murine models of transplantation. We find that that TREGs play a more central role in the maintenance of tolerance than previously appreciated. TREGs were required to constrain allospecific T cell expansion and avidity maturation during the maintenance phase of tolerance and depletion of TREGs in tolerant allograft recipients swiftly led to rejection. We also investigated the factors driving development of cell-intrinsic dysfunction in T cells persisting in tolerant transplant recipients, finding that cell-extrinsic signals from lymphocytes in the tolerant host are required to program and maintain the dysfunctional state. We also found that there is heterogeneity in the functional profile of allospecific T cells persisting during tolerance. These findings may inform strategies to improve the resilience of tolerance and develop biomarkers to track the stability of tolerance in transplant recipients.



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