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.

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，肿瘤和免疫缺陷型的T细胞免疫反应。通过抗原激活T细胞后，T细胞免疫反应的大小和持续时间由产生的IL-2量，表达的受体水平以及每个事件的时间过程确定。 IL-2受体包含三个链IL-2RA，IL-2RB和GC。伦纳德（Leonard）博士于1984年克隆了IL-2RA，他的小组在1986年发现了IL-2RB，并在1993年报道说，GC链的突变导致X链的严重合并免疫缺陷（XSCID，具有t-b+nk-nk-nk-nk-nk-nk-eTotype）在人类中。 1995年，与GC相关激酶JAK3的突变导致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基因突变引起的。基于该实验室和其他实验室的工作，GC被证明是由IL-2，IL-4，IL-7，IL-9，IL-9，IL-15和IL-21的受体共享的，并且在前一年中，由IL-2，IL-4，IL-4，IL-7和IL-15诱导和抑制了基因，并详细介绍了两种基因。据报道，IL-2对IL-7受体α链表达的表达进行负调节，这一发现具有潜在的重大影响，这对了解IL-2如何促进细胞死亡和抑制作用。 IL-7介导的抑制的机制取决于Pi 3-激酶和Akt。此外，对调节基因的基因组广泛分析揭示了IL-2，IL-7和IL-15调节了一组非常相似的基因，而IL-4调节了独特的集合。这可能与IL-2，IL-7和IL-15的STAT5蛋白激活以及IL-4对STAT6的主要激活有关。双重特异性磷酸酶，DUSP5详细描述为IL-2诱导的基因。有趣的是，DUSP5通过IL-2负面调节ERK激酶的激活，这表明IL-2介导的DUSP5激活是控制IL-2介导的ERK激活的负调节途径。在IL-7R和DUSP5上的工作继续进行。 此外，该小组继续努力研究TSLP，其结合蛋白TSPLR与GC最相关。该小组发表的说法，尽管TSLP和IL-7都具有IL-7受体α链，但TSLP和IL-7的功能是独特的。特别是，该小组报告说，小鼠TSLP在CD4 T细胞发育中起着独特的作用，而共享GC的其他细胞因子（例如IL-7和IL-15）有利于CD8 T细胞的发育。该小组以前曾发表过IL-21受体的克隆，并创建了IL-21R敲除小鼠，并证明IL-21在调节免疫蛋白酶产生中起着至关重要的作用。在过去的一年中，该组还产生了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。该小组还采用了流体动力电穿孔方法，以了解有关IL-21生物学的更多信息。该小组还使用这种方法来证明IL-21在体内的强抗肿瘤活性，并且还报道了这一发现。总体而言，这些研究有助于IL-2和相关细胞因子的信号传导方面。这些发现与免疫缺陷以及对T细胞和B细胞作用的控制相关。