IL-2 Family Cytokines and their Receptors--Structure and

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，先前已证明gc与IL-2、IL-4、IL-7、IL-9、IL-15和IL-21的受体共享。有趣的是，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。IL-2显示负调节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，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。在先前的工作中，该小组还鉴定和研究了胸腺基质淋巴细胞生成素，或TSLP，其结合蛋白TSPLR与GC最相关。该小组去年表明，尽管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CD 4 T细胞发育中起着独特的作用，而其他共享gc的细胞因子，如IL-7和IL-15，有利于CD 8 T细胞的发育。在本报告所涵盖的本年度，该小组不仅扩展了对TSLP的研究，而且还进行了重大发现，并报告了TSLP在小鼠模型系统中哮喘的发展中起着关键作用。 最后，该小组先前已经发表了IL-21受体的克隆，并建立了IL-21 R敲除小鼠，并证明IL-21在调节免疫球蛋白产生中起着关键作用。在本报告所涵盖的一年中，该小组使用IL-21转基因小鼠和流体动力学电穿孔方法来了解更多关于IL-21的生物学。该小组使用这些和体外系统来鉴定和报道IL-21具有与介导B细胞凋亡相关的主要作用，以及关键性地驱动记忆B细胞发育和终末分化为浆细胞的能力。此外，据报道，IL-21可能有助于系统性狼疮性肾炎的小鼠模型的发病机制。该小组还发现并报告了IL-21与IL-7或IL-15有效合作以增强CD 8 + T细胞的扩增，并且这在黑素瘤的鼠模型中有效增强抗肿瘤作用方面是有功能的。 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、自身免疫和癌症以及T细胞和B细胞活动的基本控制有关。

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 previously shown to be shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Interestingly, in the previous year, genes induced and repressed by IL-2, IL-4, IL-7, and IL-15 were identified and two were characterized in detail. IL-2 was shown to negatively regulate 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. In prior work, the group also had identified and studied thymic stromal lymphopoeitin, or TSLP, whose binding protein, TSPLR is most related to gc. The group showed the previous year 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. In the current year covered by this report, the group not only extended its studies on TSLP but also major discovery and reported that TSLP plays a critical role in the develop of asthma in a mouse model system. Finally, 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. In the year covered by this report, the group used IL-21 transgenic mice and the method of hydrodynamic electroporation to learn more about the biology of IL-21. The group used these and in vitro systems to identify and report that IL-21 has major actions related to mediating B-cell apoptosis and the ability to critically drive the development of memory B cells and terminal differentiation into plasma cells. Moreover, it was reported that IL-21 may contribute to the pathogenesis of a murine model of systemic lupus erythematosis. The group also discovered and reported that IL-21 potently cooperates with either IL-7 or IL-15 to augment the expansion of CD8+ T cells and that this is functional in terms of potently augmenting anti-tumor effects in a murine model of melanoma. Overall, these studies help to aspects of signaling by IL-2 and related cytokines. These findings have relevance to immunodeficiency, autoimmunity, and cancer, as well as to the basic control of T-cell and B-cell actions.