Local regulation and deletion of T cells to induce tolerance and establish long-term survival of high-risk corneal transplants

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This application requests the NEI diversity research supplement funding to an active NEI grant (NEI: #EY030283) in response to PA-21-071, to support the research training and career development of a graduate student from an underprivileged racial/ethnic and economic background. In the proposed diversity supplement, a predoctoral graduate student will lead a specific project that is directly relevant and complementary to - yet clearly distinct from - the parent NEI award. The diversity supplement proposal is tailored for the graduate student’s interest to understand how FoxP3+ T regulatory cells (Tregs) cells interact with the process of conventional T cell exhaustion. Tregs are a non-redundant CD4 T cell population required for the maintenance of self-tolerance. Additionally, the lack of functional Tregs has been demonstrated to result in lymphoproliferation and pathology. Our group has discovered a novel strategy to manipulate Treg cells in vivo. Tregs constitutively express the TNFRSF25 receptor, and we have learned that using agonists which target and signal this receptor in combination with low doses of IL-2 administered in vivo, induce a rapid and marked increase in the peripheral Treg compartment. Hence, this approach provides a unique tool to directly address a key unanswered question in the transplant field central to the process of tolerance and rejection: do Tregs impact the process of T cell exhaustion. This question is critical to develop a novel strategy to prevent allografted tissue rejection, that is driving transplant antigen specific T cells to exhaustion. Specifically, while undergoing research training and career development mentoring, the graduate student will learn to employ rigorous scientific reasoning and multiple technologies to address the follow two questions: 1) Do activated Treg cells prior/during induction of antigen specific CD8 T cells alter the exhaustion process? and 2) Can Treg cells prolong rejection while CD8 exhaustion is driven by antigen? The student will take a well-crafted curriculum designed for PhD training as well as participate in well-orchestrated career skill activities. The student will work with a mentoring team to develop an individual career development plan (IDP) and individualized mentoring plan (IMP) to guide him through the training process towards becoming independent and a creative scholar conducting interdisciplinary research in immunology and transplantation. Through the research and career training, the student is expected to be not only endowed to advance their own scientific career, but also well-prepared to face emerging challenges with creative solutions and scientific professionalism to advance society.