Il-2 Receptors--structure and function

Il-2 受体——结构和功能

• 批准号: 6967128
• 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/6967128
• 关键词: B lymphocyte; JAK kinase; T lymphocyte; biological signal transduction; cellular immunity; cytokine; cytokine receptors; electroporation; gene mutation; gene targeting; genetically modified animals; human tissue; immune response; immunodeficiency; interleukin 2; interleukin 7; laboratory mouse; leukocyte activation /transformation; lymphocyte proliferation; neoplasm /cancer immunology; protein structure function; protein tyrosine kinase; protein tyrosine phosphatase; 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, and in the previously year, genes induced and repressed by IL-2, IL-4, IL-7, and IL-15 were identified and two were characterized in detail. It was reported that IL-2 negatively regulates expression of the IL-7 receptor alpha chain expression, 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. Moreover, a genome wide analysis of regulated genes revealed IL-2, IL-7, and IL-15 regulated a very similar set of genes whereas IL-4 regulated a distinctive set. This likely relates to the activation of Stat5 proteins by IL-2, IL-7, and IL-15 and predominant activation of Stat6 by IL-4. A dual specificity phosphatase, DUSP5 was characterized in detail as an IL-2-induced gene. Interesting, DUSP5 negatively regulates activation of ERK kinases by IL-2, suggesting that IL-2-mediated activation of DUSP5 is a negative regulatory pathway for controlling IL-2-mediated ERK activation. Work on the IL-7R and DUSP5 have continued. Additionally, the group continued its effort to study TSLP, whose binding protein, TSPLR is most related to gc. The group published that although both TSLP and IL-7 share the IL-7 receptor alpha chain, the function of TSLP and IL-7 are distinctive. In particular, the group reported that mouse TSLP plays a distinctive role in CD4 T cell development whereas other cytokines that share gc, such as IL-7 and IL-15, favor the development of CD8 T cells. The group had previously published the cloning of the IL-21 receptor and had created IL-21R knockout mice and demonstrated that IL-21 plays a critical role in regulating immunoglobluin production. The group in the past year also generated IL-21 transgenic mice, and these mice were used to clarify a critical role for IL-21 in the generation of memory B cells and plasma cells. The group also employed the method of hydrodynamic electroporation to learn more about the biology of IL-21. The group also used this methodology to demonstrate strong antitumor activity of IL-21 in vivo and this finding was also reported. 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 and B-cell actions.

人们正在研究人类 IL-2 受体和相关细胞因子受体系统，以阐明正常、肿瘤和免疫缺陷状态下的 T 细胞免疫反应。 T 细胞被抗原激活后，T 细胞免疫反应的强度和持续时间取决于产生的 IL-2 量、表达的受体水平以及每个事件的时间进程。 IL-2受体包含3条链：IL-2Ra、IL-2Rb和gc。 Leonard 博士于 1984 年克隆了 IL-2Ra，他的团队于 1986 年发现了 IL-2Rb，并于 1993 年报道 gc 链突变导致 X 连锁严重联合免疫缺陷症 (XSCID，具有 T-B+NK- 表型) ）在人类中； 1995 年，gc 相关激酶 Jak3 的突变导致常染色体隐性遗传的 SCID 形式，与 XSCID 无法区分； 1998 年，T-B+NK+ SCID 是由 IL7R 基因突变引起的。根据本实验室和其他实验室的工作，gc 被证明由 IL-2、IL-4、IL-7、IL-9、IL-15 和 IL-21 受体共享，并且在前一年，鉴定了 IL-2、IL-4、IL-7 和 IL-15 诱导和抑制的基因，并对其中两个进行了详细表征。据报道，IL-2 负向调节 IL-7 受体 α 链表达，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大意义。 IL-7 介导的抑制机制取决于 PI 3-激酶和 Akt。此外，对受调节基因的全基因组分析显示，IL-2、IL-7 和 IL-15 调节一组非常相似的基因，而 IL-4 调节一组独特的基因。这可能与 IL-2、IL-7 和 IL-15 对 Stat5 蛋白的激活以及 IL-4 对 Stat6 的主要激活有关。 DUSP5 是一种双特异性磷酸酶，作为 IL-2 诱导基因进行了详细表征。有趣的是，DUSP5 通过 IL-2 负向调节 ERK 激酶的激活，表明 IL-2 介导的 DUSP5 激活是控制 IL-2 介导的 ERK 激活的负向调节途径。 IL-7R 和 DUSP5 的工作仍在继续。 此外，该小组继续努力研究TSLP，其结合蛋白TSPLR与gc最相关。该小组发表文章称，虽然TSLP和IL-7共享IL-7受体α链，但TSLP和IL-7的功能是不同的。特别是，该小组报告说，小鼠 TSLP 在 CD4 T 细胞发育中发挥着独特的作用，而其他共享 gc 的细胞因子，如 IL-7 和 IL-15，则有利于 CD8 T 细胞的发育。该小组此前发表了IL-21受体的克隆，并创建了IL-21R基因敲除小鼠，证明IL-21在调节免疫球蛋白产生中发挥着关键作用。该小组去年还培育出了IL-21转基因小鼠，这些小鼠被用来阐明IL-21在记忆B细胞和浆细胞生成中的关键作用。研究小组还采用水动力电穿孔的方法来了解更多有关IL-21生物学的信息。该小组还使用这种方法证明了 IL-21 体内强大的抗肿瘤活性，并且这一发现也被报道。总体而言，这些研究有助于 IL-2 和相关细胞因子信号传导的各个方面。这些发现与免疫缺陷以及 T 细胞和 B 细胞活动的控制相关。