Independent Cycling and Differentiation in CD4+ T cells

CD4 T 细胞的独立循环和分化

• 批准号: 6844687
• 负责人: Ian NICHOLAS Crispe
• 金额: $ 39.38万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844687
• 关键词: DNA methylation; T cell receptor; antigen presenting cell; biological signal transduction; biosynthesis; cell cycle; cell differentiation; cell growth regulation; cell proliferation; cyclin dependent kinase; enzyme linked immunosorbent assay; flow cytometry; gene induction /repression; gene targeting; genetically modified animals; helper T lymphocyte; interferon gamma; interleukin 4; interleukin 5; kinase inhibitor; laboratory mouse; leukocyte activation /transformation; messenger RNA; microarray technology; western blottings

DESCRIPTION (provided by applicant): Activated T cells undergo both proliferation, which results in clonal expansion, and differentiation, resulting in effector function. These phenomena occur together in many immune responses, but how are they linked? Some published data show that the number of divisions undergone by a CD4+ T cell is tightly correlated with differentiation and the synthesis of effector cytokines, suggesting that a molecular mechanism couples differentiation to cell division cycles. Other published data, including our own, suggest that cell division and differentiation are uncoupled. Our new preliminary data, developed in an adoptive transfer model in which the dye CFSE was used to count cell division cycles, also favor the independence of proliferation and differentiation in CD4+ T cells. To accommodate all of the data, we view the entry into S phase of the cell cycle, and the activation of the genes that encode effector cytokines, as distinct, unlinked probabilistic events. To explore this idea, we will use a model in which the synthesis of effector cytokines (IFN-gamma, IL-4 and IL-5)in CD4+ T cells occurs independent of proliferation. In Specific Aim 1, we will determine the conditions of T cell activation that result in non-cycling but functional effector T cells. In Specific Aim 2, we will define the state of cell cycle regulation in these cells, and test the hypothesis that they are arrested in the G 1 phase of the cycle, due to the action of one or more cyclin-dependent kinase inhibitors. In Specific Aim 3, we will determine whether these non-cycling but functional effector CD4+ T cells are undergoing lineage commitment to the Th1 and Th2 pathways. These studies will clarify the relationships between activation, cell division, differentiation, and lineage commitment in CD4+ T cells.

描述（由申请人提供）：激活的 T 细胞经历增殖（导致克隆扩增）和分化（导致效应功能）。这些现象在许多免疫反应中同时出现，但它们之间是如何联系的呢？一些已发表的数据表明，CD4+ T 细胞经历的分裂次数与分化和效应细胞因子的合成密切相关，这表明分子机制将分化与细胞分裂周期耦合起来。其他发表的数据，包括我们自己的数据，表明细胞分裂和分化是不相关的。我们的新初步数据是在过继转移模型中开发的，其中使用染料 CFSE 来计数细胞分裂周期，也有利于 CD4+ T 细胞增殖和分化的独立性。为了容纳所有数据，我们将进入细胞周期的 S 期以及编码效应细胞因子的基因的激活视为不同的、不相关的概率事件。为了探索这个想法，我们将使用一个模型，其中 CD4+ T 细胞中效应细胞因子（IFN-γ、IL-4 和 IL-5）的合成独立于增殖而发生。在具体目标 1 中，我们将确定 T 细胞激活的条件，从而产生非循环但有功能的效应 T 细胞。在具体目标 2 中，我们将定义这些细胞的细胞周期调节状态，并测试由于一种或多种细胞周期蛋白依赖性激酶抑制剂的作用，它们被停滞在细胞周期的 G 1 期的假设。在具体目标 3 中，我们将确定这些非循环但功能性效应 CD4+ T 细胞是否正在经历 Th1 和 Th2 途径的谱系定型。这些研究将阐明 CD4+ T 细胞的激活、细胞分裂、分化和谱系定型之间的关系。