IL-2 Family Cytokines and their Receptors-- Biology of the IL-2 system

正在研究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。1984年伦纳德博士克隆了IL-2Ra，1986年我们发现了IL-2Rb，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)。我们在1995年报道了GC相关激酶JAK3的突变导致了一种与XSCID难以区分的常染色体隐性形式的SCID，并在1998年报道了T-B+NK+SCID是由IL7R基因突变引起的。根据我们实验室和其他实验室的工作，先前发现GC由IL-2、IL-4、IL-7、IL-9、IL-15和IL-21的受体共享。我们以前也描述了由IL-2、IL-4、IL-7和IL-15诱导或抑制的基因，包括IL-7受体α链的负调控，这一发现对理解IL-2如何促进细胞死亡有意义，以及双特异性磷酸酶DUSP5的正调控，DUSP5负调控IL-2介导的ERK激酶的激活。 辅助性T细胞分化是调节宿主防御的重要过程。Th1分化对宿主防御病毒和其他细胞内病原体非常重要，Th2分化在变态反应性疾病中至关重要并与蠕虫有关，Th17分化在包括银屑病和炎症性肠病在内的一系列炎症性疾病中至关重要，我们之前的研究表明，IL-2重要调节IL-4受体的表达，并关键控制Th2分化细胞的启动。 利用过继免疫治疗的PMEL-1 T细胞受体转基因模型，我们还进行了与过继转移的效应细胞杀伤肿瘤能力相关的研究，发现来自原始CD8+T细胞而不是中央记忆CD8+T细胞的效应T细胞群体介导了优越的抗肿瘤活性。这些群体有不同的基因表达特征和发育程序，IL-2诱导的Eomesodermin在中央记忆中的表达比原始群体细胞高得多。 以前已经证明了由IL-2和IL-2靶基因诱导的双特异性磷酸酶DUSP5，并证明了DUSP5的转基因过表达导致胸腺细胞在CD4/CD8双阳性阶段的发育受阻，表明ERK激酶在这一过程中发挥了作用，DUSP5有助于免疫耐受，我们继续研究这一酶和另一种相关的重要磷酸酶。 此外，我们还协助建立了NetPath，这是一个经过精心策划的信号转导途径的公共资源，其中IL-2系统被强调为原型途径。 总体而言，这些研究有助于提高我们对GC家族细胞因子信号传导的理解。这些发现阐明了与正常和病理免疫细胞功能相关的基本分子机制，如过敏、自身免疫和癌症。

The 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, we 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. We reported 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 our 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. We also previously characterized genes that were induced or repressed by IL-2, IL-4, IL-7, and IL-15, including showing the negative regulation of the IL-7 receptor alpha chain, a finding with implications in understanding how IL-2 can promote cell death, and the positive regulation of a dual specificity phosphatase, DUSP5, that negatively regulates IL-2-mediated activation of ERK kinases. T helper cell differentiation is an important process in the regulation of host defense. Th1 differentiation is important for host defense to viruses and other intracelllular pathogens, Th2 differentiation is vital in allergic disorders and related to helminths, and Th17 differentiation is vital in a range of inflammatory disorders, including psoriasis and inflammatory bowel disease, and we previously showed that IL-2 importantly regulates expression of the IL-4 receptor and critically controls priming of cells for Th2 differentiation. Using the pmel-1 T cell receptor transgenic model of adoptive immunotherapy, we also pursued studies related to the efficacy of adoptively transferred effector cells in terms of their ability to kill turmors and found that effector T cell populations derived from naive rather than central memory CD8+ T cells mediate superior antitumor activity. These populations had distinct gene expression signatures and developmental programs, with much higher IL-2-induces expression of Eomesodermin in the central memory than naive population cells. Having previously shown that a dual specificity phosphatase, denoted DUSP5, that is induced by IL-2 and thus an IL-2 target gene and demonstrated that transgenic overexpression of DUSP5 results in a block in thymocyte development at the CD4/CD8 double positive stage, indicating a role for ERK kinases in this process and that DUSP5 contributes to immunological tolerance, we have continued work on this and another related important phosphatase. We additionally assisted in the establishment of Netpath, a public resource of curated signal transduction pathways, with the IL-2 system being highlighted as the prototype pathway. Overall, these studies help to improve our understanding of signaling by gc family cytokines. These findings clarify basic molecular mechanisms that are relevant to normal and pathological immune cell function such as allergy, autoimmunity, and cancer.