Effector Function of Autoreactive Th1 T Cells

描述(申请人提供)：我们在这个项目中的目标是通过研究细胞因子和趋化因子表达的细胞因子和趋化因子来确定致糖尿病的CD4Th1T细胞的效应功能，并确定这些介质如何在1型糖尿病自身免疫性结节模型的发病机制中起作用。我们假设巨噬细胞的募集和激活是CD4Th1T细胞效应器功能的关键组成部分，尤其是TNFa在这一过程中起着核心作用。我们的具体目标是：(1)使用一组T细胞克隆和来自TCR-TG小鼠的T细胞来确定非生理性CD4+Th1 T细胞的效应功能所必需的细胞因子和趋化因子；(2)确定CD4+Th1 T细胞的致病作用是否依赖于由Th1 T细胞招募和刺激的巨噬细胞的效应功能；以及(3)研究非生发CD4 T细胞分泌TNFa是否是诱导疾病所必需的。这些研究的意义在于，自身免疫性疾病的免疫治疗的一个主要目标是针对特定的T细胞亚群。一种直接治疗T细胞的方法是针对控制T细胞效应器功能的特定分子。我们的数据表明，致病的Th1T细胞可能具有独特的功能特征，我们的目标是使用Th1T细胞克隆进一步定义这些特性，这些克隆可以在没有其他T细胞的情况下或在定义的T细胞存在的情况下单独研究。更全面地了解Th1 T细胞亚群的效应功能将有助于我们设计更特异的T细胞靶向免疫治疗方法。

DESCRIPTION (provided by applicant): Our objective in this project is to define the effector function of diabetogenic CD4 Th1 T cells through the investigation of the cytokines and chemokines they express and determine how these mediators contribute to pathogenesis in the autoimmune NOD model of type 1 diabetes. We hypothesize that macrophage recruitment and activation is a key component of CD4 Th1 T cell effector function and that TNFa in particular has a central role in this process. Our specific aims are to: (1) use a panel of T cell clones and T cells from TCR-Tg mice to determine the cytokines and chemokines necessary for the effector function of diabetogenic CD4+ Th1 T cells; (2) determine whether the pathogenic effects of CD4+ Th1 T cells are dependent on the effector function of the macrophages recruited and stimulated by Th1 T cells; and (3) investigate whether TNFa secretion by diabetogenic CD4 T cells is necessary for induction of disease. The significance of these studies lies in the fact that a major goal of immunotherapy for autoimmune disease is to specifically target certain T cell subsets. 1 way to direct therapy to T cells is to target specific molecules that govern T cell effector function. Our data suggests that pathogenic Th1 T cells may have distinctive functional characteristics and our goal is to further define these properties using Th1 T cell clones that can be studied separately, in the absence of other T cells, or in the presence of defined T cells. A more complete understanding of the effector function of Th1 T cell subsets will help us design more specific approaches to T cell targeted immunotherapy.