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.

人们正在研究人类白细胞介素 2 受体，以了解正常细胞和肿瘤细胞中 T 细胞免疫反应的关键组成部分。 T 细胞激活后，IL-2 和 IL-2 受体被诱导； T 细胞免疫反应的强度和持续时间由产生的 IL-2 量、表达的受体水平以及这些事件的时间进程控制。 IL-2受体存在3条链：IL-2Ra、IL-2Rb和gc，其中IL-2Ra和IL-2Rb在转录水平上受到显着调节。该小组主要关注 IL-2 诱导的信号类型，特别是 STAT 蛋白（信号转导子和转录激活子）的激活，以及它们调节 IL-2Ra 基因的机制。 Stat5a 和 Stat5b 是两种密切相关的蛋白质，氨基酸一致性 > 90%，可被 IL-2 激活。一个重要的问题是这些密切相关的蛋白质的作用是否冗余或独特。为了试图澄清这个问题，我们制备了 Stat5a 和 Stat5b 转基因小鼠来重建敲除小鼠。 Stat5 蛋白在调节 CD8+ T 细胞稳态中的主要作用被发现。 Stat5a 和 Stat5b 是位于头对头方向的相邻基因。正在研究这些基因调控方面的相似性和差异性。先前报道了IL-2Ra基因中的两个IL-2反应元件，一个位于5'调节区，另一个位于第一个内含子。据报道，第二个调节元件称为 PRRIV，也是 TCR 反应元件。该元件在人类和小鼠中高度保守，位于第一个内含子中。该元件不仅受 Stat5 和 HMG-I(Y) 蛋白调节，还受 NFAT 和 AP1 位点调节。内含子元件与上游元件一起控制 IL-2Ra 基因的 IL-2 介导和 TCR 介导的调节。总之，这些研究极大地增强了我们对 IL-2R 表达和 Stat5 依赖性基因调控基础的理解。