Il-2 Receptors--structure And Function

Il-2受体--结构与功能

• 批准号: 6690574
• 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/6690574
• 关键词: JAK kinase; T lymphocyte; biological signal transduction; cellular immunity; cytokine; cytokine receptors; gene mutation; gene targeting; human tissue; interleukin 2; laboratory mouse; leukocyte activation /transformation; lymphocyte proliferation; protein structure function; protein tyrosine kinase; receptor expression; severe combined immunodeficiency

The human IL-2 receptor and related cytokine receptor systems are being studied to clarify the T cell immune response in normal, neoplastic, and immunodeficient states. Following T-cell activation by antigen, the magnitude and duration of the T-cell immune response is determined by the amount of IL-2 produced, levels of receptors expressed, and time course of each event. The IL-2 receptor contains three chains, IL-2Ra, IL-2Rb, and gc. Dr. Leonard cloned IL-2Ra in 1984, his group discovered IL-2Rb in 1986, and reported in 1993 that mutation of the gc chain results in X-linked severe combined immunodeficiency (XSCID, which has a T-B+NK- phenotype) in humans; in 1995 that mutations of the gc-associated kinase, Jak3, result in an autosomal recessive form of SCID indistinguishable from XSCID; and in 1998 that T-B+NK+ SCID results from mutations in the IL7R gene. Based on work in this lab and others, gc was shown to be shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Work on the identification of genes induced or repressed by IL-2 and related cytokines has continued and some of these are being characterized. A study on IL-2-mediated repression of IL-7 receptor alpha chain expression was accepted, a finding with potential major implications in understanding how IL-2 can promote cell death as well as repression. The mechanism of IL-7-mediated repression depends on PI 3-kinase and Akt. Other aspects of IL-2 signaling, particularly IL-2-induced serine phosphorylation are being studied, and a major serine phosphorylation site of Stat5a was identified and a manuscript was accepted for publication. Interesting, this phosphorylation did not exert a positive effect as has been found for other STAT proteins; instead, if anything, the effect could be negative. Having reported the previous year the cDNA cloning of a novel type I cytokine receptor protein which was demonstrated to be the receptor for thymic stromal lymphopoietin (TSLP), the group has worked to create a TSLPR KO mouse. The cloning of another novel cytokine receptor, now denoted as the IL-21 receptor, was previously published, creating a new field. It was previously shown that the IL-21 receptor was restricted to lymphoid cells, with expression on T-cells, NK-cells, and B-cells and that the receptor utilized the Jak-STAT pathway. In the past year, major advances were made in studying the effect of this protein in vivo, demonstrating that it plays a criical role in immunoglobulin biosynthesis. Its function in vivo is being further studied. Overall, these studies help to aspects of signaling by IL-2 and related cytokines. These findings have relevance to immunodeficiency and the control of T-cell growth.

人们正在研究人类IL-2受体和相关的细胞因子受体系统，以阐明正常、肿瘤和免疫缺陷状态下的T细胞免疫反应。在抗原激活T细胞后，T细胞免疫反应的大小和持续时间取决于产生的IL-2的数量、受体的表达水平和每个事件的时间进程。IL-2受体含有IL-2Ra、IL-2Rb和GC三条链。Leonard博士在1984年克隆了IL-2Ra，他的团队在1986年发现了IL-2Rb，并在1993年报告了GC链的突变导致人类X连锁的严重联合免疫缺陷(XSCID，具有T-B+NK表型)；1995年，GC相关激酶JAK3的突变导致了一种常染色体隐性形式的SCID，与XSCID无法区分；1998年，T-B+NK+SCID是由IL7R基因的突变引起的。根据本实验室和其他实验室的工作，IL-2、IL-4、IL-7、IL-9、IL-15和IL-21的受体共享GC。识别由IL-2和相关细胞因子诱导或抑制的基因的工作仍在继续，其中一些正在确定其特征。一项关于IL-2介导的抑制IL-7受体α链表达的研究被接受，这一发现对于理解IL-2如何促进细胞死亡和抑制具有潜在的重要意义。IL-7介导的抑制作用机制依赖于PI3K和Akt。IL-2信号的其他方面，特别是IL-2诱导的丝氨酸磷酸化正在研究中，并确定了Stat5a的一个主要丝氨酸磷酸化位点，并接受了一篇手稿以供发表。有趣的是，这种磷酸化并没有像对其他STAT蛋白那样发挥积极的作用；相反，如果说有什么影响的话，那就是这种影响可能是负面的。在前年报道了一种新的I型细胞因子受体蛋白的cdna克隆，该蛋白被证明是胸腺基质淋巴生成素(TSLP)的受体，该小组致力于创造一只TSLPR KO小鼠。另一种新的细胞因子受体的克隆，现在被称为IL-21受体，之前已经发表，开创了一个新的领域。以往的研究表明，IL-21受体仅限于淋巴样细胞，表达于T细胞、NK细胞和B细胞，并且该受体利用Jak-STAT途径。在过去的一年里，该蛋白在体内的作用研究取得了重大进展，表明它在免疫球蛋白的生物合成中起着关键作用。其在体内的作用正在进一步研究中。总体而言，这些研究有助于通过IL-2和相关细胞因子进行信号转导。这些发现与免疫缺陷和控制T细胞生长有关。