TCR/CD3 COMPLEX AND T CELL DEVELOPMENT

TCR/CD3 复合物和 T 细胞发育

• 批准号: 2736505
• 负责人: CHIH-PIN LIU
• 金额: $ 27.07万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2736505
• 关键词: CD3 molecule; T cell receptor; T lymphocyte; antibody receptor; biological signal transduction; cell differentiation; cytokine; genetically modified animals; gut associated lymphoid tissue; laboratory mouse; laboratory rabbit; mucosal immunity; protein biosynthesis; receptor expression; thymus; tissue /cell culture

The major goal of this proposal is to understand the role of T cell receptor/CD3 complexes (TCR complex) in which the zetu chain is missing or replaced with the FcRgamma molecule on T cell development and function. The zetu chain homodimer of conventional TCR complexes plays a major role for expression of the complexes and in TCR mediated signaling events. However, a number of CD4- negative normal T cells such as CD8alphaalpha+ gut intraepithelial lymphocytes express alternative TCR complexes containing only one or no zetu chain but a related molecule, FcRgamma. Interestingly, these T cells tend to express potentially autoreactive TCRs but they do not cause autoimmunity. The development and function of T cells expressing alternative TCR complex are unclear, but they may develop extrathymically. Alternative TCR complexes are generally expressed at lower levels than are conventional TCR complexes. In our transgenic mice in which all their T cells express alternative TCR complexes, the complexes are expressed at even lower levels on CD4+ than on CD8+ cells. Conversely, conventional TCR complexes are expressed at higher levels on CD4+ cells than on CD8+ cells in normal mice. It is hypothesized that FcRgamma evokes different downstream signaling pathways than does zetu and thus it may alter the behavior of T cells. Experiments in Specific Aim A are designed to determine the molecular and cellular mechanisms that regulate the expression level of TCR in T cells. These studies are to find out what signaling pathways are associated with alterative TCR complexes and their influences on TCR expression and function of T cells. Further experiments in Aim B will be performed to understand the role of alternative TCR complex on T cell development and function. The experiments will analyze the roles of thymus, the cytokine secretion patterns, and the influence of alternative TCR complex on T cell reactivity. Finally, Aim C is proposed to study gut associated lymphoid tissues which is not only the largest lymphoid organ but it plays a central role in mucosal immunity. We will generate TCR transgenic mice as an animal model to study the development of T cells bearing TCRs derived from the CD8alphaalpha+ gut intraepithelial lymphocytes which express alterative TCR complexes. The knowledge gained from the studies will provide important insights into the development of normal T cells bearing alternative TCR complexes and their roles in the systemic and mucosal immunity against tumors, infections, and in autoimmune diseases.

该提案的主要目标是了解 T 细胞的作用 缺少 zetu 链的受体/CD3 复合物（TCR 复合物） 或在 T 细胞发育过程中被 FcRgamma 分子取代 功能。 传统TCR复合物的zetu链同二聚体发挥作用 复合物表达和 TCR 介导的主要作用 信号事件。 然而，许多 CD4 阴性的正常 T 细胞 如CD8αα+肠上皮内淋巴细胞表达 仅包含一个或不包含 zetu 链但包含一个的替代 TCR 复合物 相关分子，FcRgamma。 有趣的是，这些 T 细胞倾向于 表达潜在的自身反应性 TCR，但它们不会引起 自身免疫。 T细胞表达的发育和功能 替代 TCR 复合物尚不清楚，但它们可能会发展 心外的。替代 TCR 复合物通常表达于 比传统的 TCR 复合物水平更低。 在我们的转基因 所有 T 细胞都表达替代 TCR 复合物的小鼠 复合物在 CD4+ 细胞上的表达水平甚至低于在 CD8+ 细胞上的表达水平。 相反，传统 TCR 复合物的表达水平较高 对正常小鼠的 CD4+ 细胞的影响高于对 CD8+ 细胞的影响。假设 FcRgamma 引发与 zetu 不同的下游信号通路 因此它可能会改变 T 细胞的行为。 具体实验 目标 A 旨在确定分子和细胞机制 调节 T 细胞中 TCR 的表达水平。 这些研究是 找出哪些信号通路与 TCR 变异相关 复合物及其对TCR表达和T功能的影响 细胞。 将进行目标 B 中的进一步实验以了解 替代 TCR 复合物对 T 细胞发育和功能的作用。 这 实验将分析胸腺的作用，细胞因子的分泌 模式，以及替代 TCR 复合物对 T 细胞的影响 反应性。 最后，建议目标 C 研究肠道相关淋巴组织 组织不仅是最大的淋巴器官，而且起着 在粘膜免疫中发挥核心作用。 我们将培育TCR转基因小鼠 作为研究携带 TCR 的 T 细胞发育的动物模型 源自 CD8αα+ 肠道上皮内淋巴细胞 表达替代 TCR 复合物。 从研究中获得的知识 将为正常 T 细胞的发育提供重要见解 承载替代 TCR 复合物及其在系统和 针对肿瘤、感染和自身免疫性疾病的粘膜免疫。