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

项目摘要 1型糖尿病(T1 DM)是一种以CD8 T细胞介导的破坏为特征的自身免疫性疾病 胰岛β细胞。这会导致无法产生胰岛素，从而导致终生依赖外源性 胰岛素，这是100多万美国人的情况。最近的一项II期临床试验表明，有可能推迟 使用非特异性免疫疗法促进通过T细胞传递信号的T1 DM的发病时间 受体(TCR)诱导T细胞耗竭。最近的研究表明，CD8T细胞在慢性粒细胞疾病中的作用 感染和癌症是异质性的，由产生两者的自我更新的祖细胞组成。 细胞溶解效应器和非细胞溶解耗尽细胞。然而，CD8 T细胞异质性在T1 DM和 连接TCR信号和CD8 T细胞分化的过程尚不完全清楚。更好的 对这些概念的理解对于开发更具特异性的T1 DM免疫疗法至关重要。因此， 这项研究的首要目标是研究TCR信号影响的机制。 T1 DM患者CD8T细胞分化的研究目标1将绘制出表型、克隆和活力景观图 促糖尿病的CD8 T细胞。目的2将研究是否可以选择性地诱导产生糖尿病的CD8 T细胞 由于外源性TCR刺激而筋疲力尽。该项目解决了以下方面的知识差距 免疫学和T1 DM的研究，以更好地了解CD8 T细胞在糖尿病中的作用 T1 DM的发病机制。这项工作将进一步开展旨在延缓T1 DM发病的科学和临床研究 以更有选择性的方式进行，免疫抑制不良反应较少。该项目将在 威斯康星州医学院和威斯康星州韦尔西蒂血液研究所 免疫学家和生物化学家提供多学科奖学金培训。这些导师和机构 将以严格的动手实验、有洞察力的数据分析、专注于 在发表成果时撰写手稿，以及出席以下领域的地方和国家会议 免疫学和T1 DM。这项研究的结果可以帮助我们更好地理解 CD8T细胞信号转导和分化的基本机制影响免疫病理和 T1 DM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.