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

本申请申请NEI多样性研究补充资金，以获得NEI主动拨款(NEI： #EY030283)响应PA-21-071，支持毕业生的研究培训和职业发展 来自贫困种族/民族和经济背景的学生。在拟议的多样性补编中， 博士前研究生将领导一个与YET直接相关和互补的特定项目 明显有别于-家长NEI奖。多样性补充方案是为毕业生量身定做的 学生有兴趣了解FoxP3 T调节细胞(Tregs)如何与 传统的T细胞衰竭。Tregs是维持所需的非冗余的CD4T细胞群 自我容忍的能力。此外，功能树的缺乏已被证明导致 淋巴组织增殖和病理学。我们的团队发现了一种在体内操纵Treg细胞的新策略。 Tregs结构性地表达TNFRSF25受体，我们已经了解到，使用靶向于 并向该受体发出信号，与体内注射低剂量的IL-2相结合，诱导快速而显著的 增加外周Treg隔间。因此，这种方法提供了一种独特的工具来直接处理 移植领域中对耐受和排斥过程至关重要的关键悬而未决的问题：Tregs 影响T细胞耗竭的过程。这个问题对于制定一种新的预防战略至关重要。 同种异体组织排斥反应，导致移植抗原特异性T细胞耗尽。具体地说，虽然 经过研究培训和职业发展指导，研究生将学习如何使用 严谨的科学推理和多种技术解决了以下两个问题：1)做激活 在抗原特异性CD8T细胞诱导之前/期间，Treg细胞会改变耗竭过程吗？和2)可以特雷格 细胞延长排斥反应，而CD8耗尽是由抗原驱动的？学生将选择一份精心制作的 为博士培训设计的课程，以及参加精心安排的职业技能活动。这个 学生将与指导团队合作制定个人职业发展计划(IDP)和 个人化指导计划(IMP)，指导他完成训练过程，走向独立 以及一位在免疫学和移植领域进行跨学科研究的创造性学者。通过 在科研和职业训练中，学生不仅要被赋予科学的天赋，还要推进自己的科学发展 职业生涯，但也做好了充分准备，以创造性的解决方案和科学的 以专业精神推动社会进步。

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.