Il2 Receptors--molecular Regulation

Il2受体--分子调控

• 批准号: 6690575
• 负责人: Warren J Leonard
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6690575
• 关键词: T lymphocyte; biological signal transduction; cellular immunity; cytokine receptors; gene targeting; genetic regulation; genetically modified animals; human tissue; interleukin 2; laboratory mouse; leukocyte activation /transformation; neoplasm /cancer immunology; protein structure function; receptor expression; tissue /cell culture; transcription factor

The human interleukin-2 receptor is being studied to understand critical components of the T cell immune response in normal and neoplastic cells. Following T-cell activation, IL-2 and IL-2 receptors are induced; the magnitude and duration of the T-cell immune response is controlled by the amount of IL-2 produced, the levels of receptors expressed, and the time course of these events. Three chains of the IL-2 receptor exist, IL-2Ra, IL-2Rb, and gc, with IL-2Ra and IL-2Rb being significantly regulated at the level of transcription. The group has focused primarily on the types of signals induced by IL-2, particularly the activation of STAT proteins (signal transducers and activators of transcription), and the mechanism by which they regulate the IL-2Ra gene. Stat5a and Stat5b are two closely related proteins with >90% amino acid identity that are activated by IL-2. An important issue is whether these closely related proteins are redundant or distinctive in their actions. To attempt to clarify this issue, Stat5a and Stat5b transgenic mice have been generated to reconstitute the knockout mice. A major role for Stat5 proteins in regulating CD8+ T cell homeostasis was discovered. Stat5a and Stat5b are adjacent genes located in a head-to-head orientation. Aspects of similarities vs. differences in regulation of these genes is being studied. Two IL-2 response elements in the IL-2Ra gene were previously reported, one in the 5' regulatory region and the other in the first intron. This second regulatory element, denoted PRRIV, was reported to be a TCR response element as well. This element is highly conserved in humans and mice and is located in the first intron. This element is regulated not only by Stat5 and HMG-I(Y) proteins but also by NFAT and AP1 sites. Together with the upstream elements, the intronic element controls IL-2-mediated and TCR-mnediated regulation of the IL-2Ra gene. Together, these studies substantially enhance our understanding of the basis of IL-2R expression and Stat5-dependent gene regulation.

正在研究人白细胞介素-2受体，以了解正常和肿瘤细胞中T细胞免疫反应的关键成分。 T细胞激活后，诱导IL-2和IL-2受体。 T细胞免疫反应的大小和持续时间受到产生的IL-2的量，表达的受体水平以及这些事件的时间过程的控制。 IL-2受体的三个链，IL-2RA，IL-2RB和GC存在，IL-2RA和IL-2RB在转录水平下受到显着调节。该组主要集中在IL-2诱导的信号类型上，尤其是STAT蛋白的激活（信号换能器和转录的激活因子）以及调节IL-2RA基因的机制。 STAT5A和Stat5b是两个密切相关的蛋白质，其氨基酸身份> 90％，被IL-2激活。一个重要的问题是这些密切相关的蛋白质在其作用中是多余的还是独特的。为了澄清这个问题，已经生成了STAT5A和Stat5b转基因小鼠来重建淘汰小鼠。发现STAT5蛋白在调节CD8+ T细胞稳态中的主要作用。 STAT5A和STAT5B是位于正面方向的相邻基因。正在研究这些基因调节的相似性与差异的各个方面。先前报道了IL-2RA基因中的两个IL-2响应元件，一个在5'调节区域，另一个在第一个内含子中。据报道，第二个调节元件（表示为PRRIV）也是TCR响应元件。该元素在人类和小鼠中是高度保守的，并且位于第一个内含子中。该元素不仅受STAT5和HMG-I（Y）蛋白的调节，还由NFAT和AP1位点调节。与上游元件一起，内含子元件控制IL-2介导的IL-2RA基因的TCR介导的调节。总之，这些研究大大增强了我们对IL-2R表达和STAT5依赖性基因调控基础的理解。