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

IL-2家族细胞因子及其受体--IL-7/TSLP系统的生物学

• 批准号: 8149525
• 负责人: Warren J Leonard
• 金额: $ 67.6万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8149525
• 关键词: Biology; Family; Interleukin-2; System; cytokine; receptor

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.

研究人员正在研究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t细胞被抗原激活后，t细胞免疫反应的大小和持续时间取决于产生的IL-2的量、受体表达的水平和每个事件的时间过程。IL-2受体包含三条链，IL-2Ra、IL-2Rb和gc。Leonard博士于1984年克隆了IL-2Ra，我们于1986年发现了IL-2Rb，并于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SCID的常染色体隐性形式与XSCID难以区分，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人的工作，gc先前被证明是由IL-2， IL-4, IL-7, IL-9， IL-15和IL-21的受体共享的。在之前的工作中，我们也鉴定和研究了胸腺基质淋巴生成素（TSLP），其结合蛋白TSLPR与gc关系最为密切，我们发现尽管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CD4 T细胞的发育，而IL-7和IL-15（也共享gc）有利于CD8 T细胞的发育，并且在小鼠模型系统中TSLP在过敏性哮喘的发展中起关键作用。