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

点击翻译按钮获取中文摘要

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.