Il-2 Receptors--structure and function

人类IL-2受体和相关的细胞因子受体系统正在被研究，以阐明正常、肿瘤和免疫缺陷状态下的T细胞免疫反应。在t细胞被抗原激活后，t细胞免疫反应的大小和持续时间取决于产生的IL-2的量、受体表达的水平和每个事件的时间过程。IL-2受体包含三条链，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年报道了gc链突变导致人类x连锁严重联合免疫缺陷（XSCID，具有T-B+NK-表型）。1995年，gc相关激酶Jak3突变导致常染色体隐性SCID与XSCID难以区分；1998年发现T-B+NK+ SCID是由IL7R基因突变引起的。根据本实验室和其他人的工作，gc被证明是由IL-2、IL-4、IL-7、IL-9、IL-15和IL-21的受体共享的，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，并对其中两个基因进行了详细的表征。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介导的抑制机制依赖于pi3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调控的是一组非常相似的基因，而IL-4调控的是一组与众不同的基因。这可能与IL-2、IL-7和IL-15激活Stat5蛋白和IL-4激活Stat6蛋白有关。DUSP5是一种双特异性磷酸酶，是il -2诱导的基因。有趣的是，DUSP5负调控IL-2对ERK激酶的激活，提示IL-2介导的DUSP5激活是控制IL-2介导的ERK激活的负调控途径。IL-7R和DUSP5的研发工作仍在继续。

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.