Il-2 Receptors--structure And Function

人IL-2受体和相关的细胞因子受体系统正在研究中，以澄清正常，肿瘤和免疫缺陷状态下的T细胞免疫应答。在T细胞被抗原激活后，T细胞免疫应答的幅度和持续时间由产生的IL-2的量、表达的受体水平和每个事件的时间过程决定。IL-2受体含有三条链，IL-2 Ra、IL-2 Rb和gc。伦纳德博士于1984年克隆了IL-2 Ra，他的小组于1986年发现了IL-2 Rb，并于1993年报道了GC链突变导致X连锁严重联合免疫缺陷在1995年，GC相关激酶Jak 3的突变导致与XSCID无法区分的常染色体隐性形式的SCID;在1998年，T-B+NK+ SCID是由IL 7 R基因突变引起的。基于本实验室和其他实验室的工作，已证明IL-2、IL-4、IL-7、IL-9、IL-15和IL-21的受体共享gc。 在过去的一年中，IL-2，IL-4，IL-7和IL-15诱导和抑制的基因被鉴定出来，其中两个基因被详细描述。据报道，IL-2负调节IL-7受体α链表达的表达，这一发现对理解IL-2如何促进细胞死亡以及抑制具有潜在的重要意义。IL-7介导的抑制机制依赖于PI 3-激酶和Akt。此外，对调控基因的全基因组分析显示IL-2、IL-7和IL-15调控非常相似的基因组，而IL-4调控独特的基因组。这可能与IL-2、IL-7和IL-15对Stat 5蛋白的激活以及IL-4对Stat 6的主要激活有关。双特异性磷酸酶DUSP 5被详细表征为IL-2诱导的基因。有趣的是，DUSP 5负调节IL-2对ERK激酶的激活，这表明IL-2介导的DUSP 5激活是控制IL-2介导的ERK激活的负调节途径。还报道了Stat 5a的一个主要丝氨酸磷酸化位点的鉴定。有趣的是，这种磷酸化并没有像其他STAT蛋白那样产生积极的影响;相反，如果有的话，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最相关。该小组此前发表了IL-21受体的克隆。在过去的一年中，该实验室报告了IL-21 R基因敲除小鼠的建立，并证明IL-21在调节免疫球蛋白产生方面起着关键作用。有趣的是，IL-21似乎负调节IgE的产生，而它对IgG 1的产生是必不可少的，并且使用IL-4 KO小鼠的研究也揭示了IL-4和IL-21一起全面调节免疫球蛋白的产生。鉴于先前的工作表明，缺陷的IL-7信号传导解释了XSCID中的T细胞缺陷，缺陷的IL-15信号传导解释了XSCID中的NK细胞缺陷，这些研究表明，IL-4和IL-21信号传导中的缺陷的组合解释了XSCID和Jak 3缺陷的SCID中的B细胞缺陷。总的来说，这些研究有助于IL-2和相关细胞因子的信号转导方面。这些发现与免疫缺陷和T细胞生长的控制有关。

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.