IL-2 Family Cytokines and their Receptors--Biology of the IL-7/TSLP Systems

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，我们于1986年发现了IL-2 Rb，并于1993年报道了人类中GC链突变导致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Jak 3的突变导致与XSCID难以区分的常染色体隐性形式的SCID，并且在1998年报道了T-B+NK+ SCID由IL 7 R基因突变引起。基于我们实验室和其他实验室的工作，先前显示gc被IL-2、IL-4、IL-7、IL-9、IL-15和IL-21的受体共享。在先前的工作中，我们也鉴定和研究了胸腺基质淋巴细胞生成素（TSLP），其结合蛋白TSLPR与gc最相关，并且我们表明，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。我们发现，TSLP促进CD 4 T细胞的发展，而IL-7和IL-15，也共享gc，有利于CD 8 T细胞的发展，TSLP在小鼠模型系统中过敏性哮喘的发展中起着关键作用。 在与Lodish实验室的合作中，我们先前报道了TSLPR的克隆，并证明了TSLP，与文献的意义相反，在人类和小鼠中通过CD 4 + T细胞发挥其一些主要作用，并且先前表明TSLP和IL-7，共享IL-7 Ra作为受体组分，都驱动调节性T细胞的发育，TSLP也通过CD 8 + T细胞上的受体进行信号传导。 近年来，我们对TSLP的信号转导机制进行了深入研究，并进一步阐明了TSLP和gc家族细胞因子在细胞存活和增殖中的作用。此外，在一项合作研究中，显示患有特应性皮炎但不患有银肩病或扁平苔藓的患者具有Notch受体（一种关键转录因子信号传导途径）的表达的显著降低，并且角质形成细胞中Notch的缺失诱导TSLP的产生，TSLP涉及与骨髓增生性病症相关的特应性皮炎。 总体而言，这些研究增加了我们对gc家族细胞因子和TSLP信号传导的理解，阐明了与免疫缺陷、过敏、自身免疫和癌症以及与淋巴稳态相关的分子机制。

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. In prior work, we also had identified and studied thymic stromal lymphopoeitin (TSLP), whose binding protein, TSLPR, is most related to gc, and we showed that although both TSLP and IL-7 share the IL-7 receptor alpha chain, the function of TSLP and IL-7 are distinctive. We showed that TSLP promotes CD4 T cell development whereas IL-7 and IL-15, which also share gc, favor CD8 T cell development, and that TSLP plays a critical role in the develop of allergic asthma in a mouse model system. In collaboration with the Lodish lab, we previously reported the cloning of TSLPR and demonstrated that TSLP, counter to the sense of the literature, exerted some of its major actions via CD4+ T cells in both humans and mice, and previously showed that TSLP and IL-7, which share IL-7Ra as a receptor component, both drive the development of regulatory T cells, and that TSLP also signals via receptors on CD8+ T cells. In the past year, we focused on the mechanism of signal transduction of TSLP and also further clarified its role and that of gc family cytokines on survival and proliferation. Moreover, in a collaborative study, it was shown that patients suffering from atopic dermatitis but not psoriasis or lichen planus had a marked reduction of expression for the receptor for Notch, a key transcription factor signaling pathway and that the loss of Notch in keratinocytes induces the production of TSLP, which is implicated in atopic dermatitis that is associated with a myeloproliferative disorder. Overall, these studies have increase our understanding of signaling by gc family cytokines and TSLP, clarifying molecular mechanisms that are relevant to immunodeficiency, allergy, autoimmunity, and cancer, as well as related to lymphoid homeostasis.