ANERGY AND SIGNALING IN MURINE T CELL SUBSETS

鼠 T 细胞亚群的无能和信号传导

• 批准号: 6099749
• 负责人: FRANK W. FITCH
• 金额: $ 17.7万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6099749
• 关键词: CD28 molecule; CD3 molecule; anergy; biological signal transduction; cytokine; genetically modified animals; guanosinetriphosphatases; helper T lymphocyte; laboratory mouse; leukocyte activation /transformation; mitogen activated protein kinase; molecular cloning; polymerase chain reaction; protein biosynthesis; protein kinase; tissue /cell culture

complete activation of T lymphocytes requires, in addition to stimulation via the TCR/CD3 complex, participation of one or more costimulator molecules. For Th1 cells, ligation of the TCR complex in the absence of costimulation results in anergy, a state characterized by deficient IL-2 production and proliferation. One costimulator molecule for IL-2-producing T cells is CD28, which interacts with the ligands B7-1 and B7-2 expressed on antigen-presenting cells and other cell type. CTLA4 is a homologous molecule expressed on activated T cells that also binds to B7-1 and B7-2 but which may have a negative function for T cell activation. In contrast to Th1 cells, less is known about the costimulatory requirements of IL-4 producing Th2 cells. The principal goals of this Project are to characterize the signaling defects in anergic Th1 clones that correlate with the anergic state, to determine if the observed changes are causally related to an inability to produce IL-2, to identify the normal signaling pathway(s) that mediate the functions of CD28, to analyze the biochemical consequences of CTLA4 ligation on the functions of Th1 and Th2 cells, and to identify and characterize the costimulator molecule(s) for Th2 cells . These studies will take advantage of a panel of well- defined Th1 and Th2 clones generated in our laboratory, as well as a series of transgenic and knockout mice. The focus will be on positive and negative regulation of the signaling studies will be aided by a panel of tumor cell transfectants that express permutations of I-Ad, B7-1, B7-2, and ICAM-1. Inasmuch as cytokine production and proliferation by established Th2 clones are unaffected by CD28/B7 blockage, additional cistimulator molecules that regulate the growth of Th2 cells will be identified and characterized. Once identified, the signaling pathways triggered by these ligands will be contrasted with those induced by CD28 and IL-1. Collectively, these studies should provide a more thorough understanding of the function of cistimulator receptors and their biochemical signals in the control of T cell activation versus inactivation, and in the regulation of distinct T cell subsets. Such information should have broad implications for transplantation, autoimmunity, and the immune response against cancers.

T淋巴细胞的完全活化除了需要 通过TCR/CD3复合物的刺激，一个或多个 共刺激分子 对于Th1细胞，TCR复合物在细胞中的连接 缺乏共刺激导致无反应性，这种状态的特征是 缺乏IL-2产生和增殖。 一个共刺激器 产生IL-2的T细胞的分子是CD28，它与 在抗原呈递细胞上表达的配体B7 - 1和B7 - 2以及其他 细胞类型。 CTLA 4是一种在活化T细胞上表达的同源分子， 也与B7 - 1和B7 - 2结合，但可能具有阴性 T细胞活化的功能。 与Th1细胞相比， 关于IL-4产生Th2细胞的共刺激需求。 该项目的主要目标是表征信号 与无反应性状态相关的无反应性Th1克隆缺陷， 确定观察到的变化是否与无法 以产生IL-2，以鉴定正常的信号传导途径， 介导CD28的功能，分析其生物化学特性， CTLA4连接对Th1和Th2功能的影响 细胞，并鉴定和表征共刺激分子， Th2细胞 这些研究将利用一组良好的- 在我们的实验室中产生的定义的Th1和Th2克隆，以及 一系列转基因和基因敲除小鼠。 重点将放在积极的 和负调控的信号研究将有助于一个 一组表达I-Ad排列的肿瘤细胞转染子， B7 - 1、B7 - 2和ICAM-1。 由于细胞因子的产生和 已建立的Th2克隆的增殖不受CD28/B7的影响 阻断，额外的顺式刺激分子， 将鉴定和表征Th2细胞。 一旦确定， 由这些配体触发的信号通路将与 由CD28和IL-1诱导。 总的来说，这些研究应该 更深入地了解顺式刺激剂的功能 受体及其生化信号在T细胞调控中的作用 活化与失活，以及不同T细胞的调节 子集 这些信息应具有广泛的影响， 移植，自身免疫，以及针对 癌的