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

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，先前已发现IL-2、IL-4、IL-7、IL-9、IL-15和IL-21的受体共享GC。有趣的是，在前一年，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。IL-2可以负向调节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。在之前的工作中，该小组还鉴定和研究了胸腺基质淋巴生成素，或TSLP，其结合蛋白TSPLR与GC关系最密切。该小组前一年的研究表明，尽管TSLP和IL-7都共享IL-7受体阿尔法链，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CD4T细胞发育中发挥着独特的作用，而其他共享GC的细胞因子，如IL-7和IL-15，有利于CD8T细胞的发育。在本报告所涵盖的这一年中，该小组不仅扩大了对TSLP的研究，而且还取得了重大发现，并报告了TSLP在小鼠模型系统中在哮喘发生中的关键作用。 最后，该小组之前发表了IL-21受体的克隆，并创造了IL-21R基因敲除小鼠，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。在本报告所涵盖的一年中，该小组使用了IL-21转基因小鼠和流体动力电穿孔的方法来了解更多关于IL-21的生物学知识。该小组使用这些和体外系统来识别和报告IL-21具有与介导B细胞凋亡和关键驱动记忆B细胞的发育和最终分化为浆细胞的能力有关的主要作用。此外，据报道，IL-21可能参与了系统性红斑狼疮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有效地合作，以增强CD8+T细胞的扩张，并在黑色素瘤小鼠模型中有效地增强了抗肿瘤效果。 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、自身免疫和癌症有关，也与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.