Il-2 Receptors--structure And Function

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。 在过去的一年里，由IL-2、IL-4、IL-7和IL-15诱导和抑制的基因被鉴定出来，其中两个被详细描述。据报道，IL-2负性调节IL-7受体α链的表达，这一发现对理解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。此外，对调控基因的全基因组分析显示，IL-2、IL-7和IL-15调控一组非常相似的基因，而IL-4调控一组不同的基因。这可能与IL-2、IL-7和IL-15激活Stat5蛋白和IL-4主要激活Stat6有关。双特异性磷酸酶DUSP5是一种IL-2诱导的基因。有趣的是，DUSP5负性调节IL-2激活ERK激酶，提示IL-2介导的DUSP5激活是控制IL-2介导的ERK激活的负性调节途径。此外，还发现了Stat5a的一个主要丝氨酸磷酸化位点。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。该小组继续努力研究TSLP，其结合蛋白TSPLR与GC关系最密切。该小组此前发表了IL-21受体的克隆。在过去的一年里，该实验室报告了IL-21R基因敲除小鼠的创建，并证明了IL-21在调节免疫球蛋白产生方面发挥着关键作用。有趣的是，IL-21似乎负向调节IgE的产生，而它对IgG1的产生是必不可少的，而且使用IL-4 KO小鼠的研究表明，IL-4和IL-21共同调节免疫球蛋白的产生。以前的研究表明，IL-7信号缺陷解释了XSCID中T细胞缺陷，IL-15信号缺陷解释了XSCID中NK细胞缺陷，而这些研究表明，IL-4和IL-21信号缺陷共同解释了XSCID和JAK3缺陷SCID中B细胞缺陷。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。

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. In the past 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. The identification of a major serine phosphorylation site of Stat5a was also reported. 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. The group continued its effort to study TSLP, whose binding protein, TSPLR is most related to gc. The group previously published the cloning of the IL-21 receptor. In the past year, the lab reported the creation of IL-21R knockout mice and demonstrated that IL-21 plays a critical role in regulating immunoglobluin production. Interestingly, IL-21 appears to negatively regulate IgE production, whereas it is essential for IgG1 production and studies also using IL-4 KO mice reveal that IL-4 and IL-21 together globally regulate immunoglobulin production. Whereas previous work indicated that defective IL-7 signaling explained the T-cell defect in XSCID and defective IL-15 signaling explained the NK cell defect in XSCID, these studies indicate that a combination of defects in IL-4 and IL-21 signaling explain the B cell defects in XSCID and in Jak3-deficient SCID. 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.