MECHANISMS OF T CELL TOLERANCE VS AUTOIMMUNITY IN VIVO

描述(由申请人提供)：本项目的目标是 分析决定外周T细胞选择的机制 对模型全身和组织受限的耐受性和自身免疫性疾病 自身抗原。我们将开发一组抗原受体转基因小鼠 耐受途径(Fas，CTLA-4)中携带突变，小鼠表达 组织(胰岛β细胞)中的同源抗原 发行，以解决以下具体目标。 1.这个目标背后的假设是，不同的机制 外周耐受，如Fas介导的缺失和CTLA4介导的无能， 可能负责保持对不同类型的自我的容忍 抗原，并防止自身免疫的不同表现。我们会 明确T细胞缺失和无能在维持耐受性中的作用 组织和系统抗原，使用T细胞转化为抗原表达 收件人。我们将研究细胞的存活率和功能反应性。 正常T细胞和Fas/FasL或CTLA-4突变的细胞，以定义 自身抗原相遇的后果和这些机制的失败 宽容。 2.自身免疫中的细胞因子失调。在这个目标中，我们将研究 IL-2和TGF-β两种细胞因子在自身抗原耐受中的作用我们 将研究缺乏IL-2或IL-2R的TCR转基因T细胞的相互作用， 或表达显性阴性形式的转化生长因子-β受体，与同源 体内的抗原。我们将定义自身免疫反应的模式，以及 T细胞中与自身免疫发展相关的缺陷。 3.体内耐受诱导机制。在这个目标中，我们将分析 耐受的生化机制，最初是通过分离具有 体内遇到的自身抗原及其基因模式的确定 表情。我们还将在触发T细胞的T细胞中表达选定的基因 特定的生化途径，并确定这些基因的表达 干扰耐受性诱导。 4.感染在自身免疫中的作用。检查感染对人类健康的影响 引发自身免疫反应，并询问微生物是否可以通过诱导 通过共刺激分子或分子模拟，我们将表达特定的蛋白质 原型病毒(柯萨奇)中的抗原，并确定病毒是否以及如何 在有和没有抗原的情况下，对该抗原的耐受性在 纸巾。因此，这个项目将解决关于 体内T细胞耐受性的调控及其可能的机制 系统性和组织性自身免疫性疾病。

Description (provided by applicant): The objective of this project is to analyze the mechanisms that determine the choice between peripheral T cell tolerance and autoimmune disease against model systemic and tissue-restricted self antigens. We will exploit a panel of antigen receptor transgenic mice carrying mutations in tolerance pathways (Fas, CTLA-4), and mice expressing the cognate antigens in tissues (pancreatic islet beta cells) and in the circulation, to address the following specific aims. 1. The hypothesis underlying this aim is that different mechanisms of peripheral tolerance, such as Fas-mediated deletion and CTLA4-mediated anergy, may be responsible for maintaining tolerance to different types of self antigens, and preventing different manifestations of autoimmunity. We will define the roles of T cell deletion and anergy in maintaining tolerance to tissue and systemic antigens, using T cell transfers into antigen-expressing recipients. We will examine the survival and functional responsiveness of normal T cells and cells with mutations in Fas/FasL or CTLA-4, to define the consequences of self antigen encounter and the failure of these mechanisms of tolerance. 2. Cytokine dysregulation in autoimmunity. In this aim we will examine the roles of two cytokines, IL-2 and TGF-beta in tolerance to self antigens. We will examine the interactions of TCR transgenic T cells lacking IL-2 or IL-2R, or expressing a dominant negative form of the TGF-beta receptor, with cognate antigens in vivo. We will define the patterns of autoimmune reactions, and the defects in T cells that correlate with the development of autoimmunity . 3. Mechanisms of tolerance induction in vivo. In this aim, we will analyze the biochemical mechanisms of tolerance, initially by isolating T cells that have encountered self antigens in vivo and defining their patterns of gene expression. We will also express selected genes in T cells that trigger specific biochemical pathways, and determine if expression of these genes interferes with tolerance induction. 4. Role of infections in autoimmunity. To examine the effects of infections in triggering autoimmune reactions, and ask if microbes may do this by inducing costimulators or by molecular mimicry, we will express defined protein antigens in a prototype virus (Coxsackie), and determine if and how the virus with and without the antigen breaks tolerance to that antigen expressed in tissues. Thus, this project will address fundamental questions about the control of T cell tolerance in vivo and the mechanisms that may lead to systemic and tissue autoimmune diseases.