Mechanistic study of TCR signaling strength in CD8 T cell differentiation during pathogenesis of T1DM

项目摘要 1型糖尿病（T1DM）是一种以CD8 T细胞介导的破坏为特征的自身免疫性疾病 胰腺β细胞的数量这导致不能产生胰岛素，从而终身依赖外源性胰岛素。 胰岛素，就像超过100万美国人一样。最近的一项II期临床试验表明， 使用通过T细胞促进信号传导的非特异性免疫疗法的T1DM发作时间 受体（TCR）以诱导T细胞耗竭的状态。最近的研究表明，慢性炎症中的CD8 T细胞 感染和癌症是异质性的，由自我更新的祖细胞组成， 溶细胞效应细胞和非溶细胞耗竭细胞。然而，T1DM患者的CD8 T细胞异质性和T1DM患者的CD8 T细胞异质性与T1DM患者的CD8 T细胞异质性相关。 连接TCR信号传导和CD8 T细胞分化的过程尚未完全理解。更好的 理解这些概念对于开发更特异的T1DM免疫疗法至关重要。因此，我们认为， 这项研究的首要目标是研究TCR信号影响 T1DM中的CD8 T细胞分化。目标1将绘制表型，克隆，和充满活力的景观， 致糖尿病的CD8 T细胞。目的2：探讨糖尿病性CD8 T细胞是否能被选择性地 通过外源性TCR刺激而耗尽。本项目解决以下方面的知识差距： 免疫学和T1DM研究，以便更好地了解CD8 T细胞在T1DM中的作用。 T1DM的发病机制。这项工作将进一步开展旨在延迟T1DM发病的科学和临床研究 具有更少的免疫抑制副作用。该项目将在 威斯康星州医学院和Versiti威斯康星州血液研究所， 免疫学家和生物化学家提供多学科研究金培训。这些导师和机构 将提供严格的动手实验，有见地的数据分析，重点突出的形式优秀的培训 在发表成果时撰写手稿，并出席地方和国家会议， 免疫学和T1DM。这项研究的结果可能会导致更好地了解如何 CD8 T细胞信号传导和分化的基本机制影响免疫病理学， T1DM的病程，符合NIDDK的使命。

Project Summary Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by CD8 T cell-mediated destruction of pancreatic beta cells. This leads to an inability to produce insulin and thus a lifelong dependence on exogenous insulin, as is the case for over 1 million Americans. A recent phase II clinical trial has shown it is possible to delay the time to onset of T1DM using a non-specific immunotherapy that promotes signaling through the T cell receptor (TCR) to induce a state of T cell exhaustion. Recent studies have shown that CD8 T cells in chronic infection and cancer are heterogeneous, consisting of self-renewing progenitor cells that give rise to both cytolytic effector and non-cytolytic exhausted cells. However, CD8 T cell heterogeneity in T1DM and the processes connecting TCR signaling and CD8 T cell differentiation are not yet fully understood. A better understanding of these concepts is vital for developing more specific immunotherapies for T1DM. Therefore, the overarching goal of this fellowship is to investigate the mechanisms by which TCR signaling affects CD8 T cell differentiation in T1DM. Aim 1 will map the phenotypic, clonal, and energetic landscapes of diabetogenic CD8 T cells. Aim 2 will investigate whether diabetogenic CD8 T cells can be selectively exhausted via exogenous TCR stimulation. This project addresses knowledge gaps at the intersection of immunology and T1DM research in order to obtain a better understanding of the role of CD8 T cells in the pathogenesis of T1DM. This work will further scientific and clinical studies that aim to delay the onset of T1DM in a more selective manner with fewer immunosuppressive adverse effects. This project will be conducted at the Medical College of Wisconsin and the Versiti Wisconsin Blood Research Institute with the mentorship of 6 immunologists and biochemists to provide multidisciplinary fellowship training. These mentors and institutions will provide excellent training in the form of rigorous hands-on experiments, insightful data analysis, focused manuscript writing when publishing results, and attendance at local and national meetings in the fields of immunology and T1DM. The results of this fellowship could lead to an improved understanding of how fundamental mechanisms of CD8 T cell signaling and differentiation impact the immunopathology and disease course of T1DM, in line with the mission of NIDDK.