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的突变导致了与XSCID难以区分的常染色体隐性形式的SCID；1998年，T-B+NK+SCID是由IL7R基因的突变引起的。在过去的一年里，该小组报告了成功的GC基因敲除小鼠缺陷的基因治疗重建，建立了小鼠的原理证明，作为迈向人类XSCID基因治疗的一步。有趣的是，这种校正可以发生在人的GC上，这表明人的GC有能力与小鼠细胞因子和这些小鼠细胞因子的其他受体成分进行功能性合作。该小组还报道，细胞因子信号的负调控因子CIS(细胞因子诱导的SH2包含蛋白；也称为CIS1)与IL-2RB结合并抑制IL-2信号转导，并推进其对相关蛋白质JAB/SOCS1/SSI-1的研究。鉴定IL-2诱导基因的工作仍在继续。最后，该小组报道了一种新的I型细胞因子受体蛋白的cDNA克隆，该蛋白被证明是胸腺基质淋巴生成素(TSLP)的受体。有趣的是，像IL-7一样，TSLP也是从基质中衍生出来的。其受体由IL-7Ra+TSLPR组成，而IL-7通过由IL-7Ra+GC组成的受体传递信号。这些发现有助于解释IL-7ra缺陷小鼠(因此缺乏通过IL-7和TSLP的信号)比IL-7缺陷小鼠(只有IL-7信号缺陷)更大的缺陷。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. During the past year, the group reported the successful gene-therapeutic reconstitution of the defect in gc-knockout mice, establishing proof of principal in mice as a step towards the human gene therapy for XSCID. Interestingly, the correction could occur with human gc, indicating the ability of human gc to functional cooperate with murine cytokines and the other receptor components of these murine cytokines. The group also reported that a negative regulator of cytokine signaling, CIS (cytokine-inducible SH2 containing protein; also called CIS1) associates with IL-2Rb and inhibits IL-2 signaling and advanced its work on a related protein, denoted JAB/SOCS1/SSI-1. Work on the identification of IL-2-inducible genes continued. Finally, the group reported the cDNA cloning of a novel type I cytokine receptor protein which was demonstrated to be the receptor for thymic stromal lymphopoietin (TSLP). Interestingly, like IL-7, TSLP is derived from stroma. Its receptor consists of the IL-7Ra + TSLPR, whereas IL-7 signals through a receptor comprising IL-7Ra + gc. These findings help to explain the greater defect in IL-7Ra-deficient mice (which thereby lack signaling via IL-7 and TSLP) than in IL-7-deficient mice (in which only IL-7 signaling is defective). 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.