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: 7735034
• 负责人: Warren J Leonard
• 金额: $ 66.78万
• 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/7735034
• 关键词: Autoimmunity; B-Lymphocytes; Binding Proteins; Biological Models; Biology; CD27 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cells; Cloning; Collaborations; Cytokine Receptors; Development; Event; Exhibits; Extrinsic asthma; Family; Genes; Human; Hypersensitivity; IL7R gene; Immune response; Immune system; Immunologic Deficiency Syndromes; Infection; Interleukin 2 Receptor; Interleukin 2 Receptor Gamma; Interleukin 7 Receptor; Interleukin-15; Interleukin-2; Interleukin-4; Interleukin-7; Interleukin-9; Listeria monocytogenes; Literature; Lymphocyte; Malignant Neoplasms; Mediating; Molecular; Mus; Mutate; Mutation; Phenotype; Phosphotransferases; Play; Reporting; Role; Signal Transduction; System; T-Cell Development; T-Lymphocyte; Time; Transgenic Mice; Work; X-Linked Severe Combined Immunodeficiency; alpha chain interleukin-7 receptor; base; cytokine; human TSLP protein; human disease; improved; interleukin-17C; interleukin-21; keratinocyte growth factor; mouse model; neoplastic; prevent; 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. In the past year, we showed that TSLP and IL-7, which share IL-7Ra as a receptor component, both drive the development of regulatory T cells. Interestingly IL-7Ra is essential for the development of these cells but mice deficient in either IL-7 or TSLPR developed relatively normal numbers of these cells. Thus, these two cytokines appear to exhibit partially overlapping actions for IL-7 and TSLP. We also showed that TSLP is not sufficient to mediate the thymopoietic effects of keratinocyte growth factor. The IL-7R alpha chain is the chain shared by both TSLP and IL-7. In another study, we generated IL-7Ra transgenic mice which were used to show that constitutive expression of IL-7Ra was insufficient to support increased expansion or prevent contraction of lymphocytes during infection with Listeria monocytogenes. Overall, these studies help to improve our understanding of signaling by gc family cytokines and of TSLP. These findings clarify molecular mechanisms that are relevant to immunodeficiency, allergy, autoimmunity, and cancer, as well as to the basic control of T-cell and B-cell actions.

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。 与Lodish实验室合作，我们先前报道了TSLPR的克隆，并证明TSLP与文献相反，通过人类和小鼠中的CD 4 + T细胞发挥其一些主要作用。在过去的一年中，我们发现TSLP和IL-7，它们共享IL-7 Ra作为受体成分，都驱动调节性T细胞的发育。有趣的是，IL-7 Ra对于这些细胞的发育是必不可少的，但是IL-7或TSLPR缺陷的小鼠发育了相对正常数量的这些细胞。因此，这两种细胞因子似乎对IL-7和TSLP表现出部分重叠的作用。 我们还发现TSLP不足以介导角质细胞生长因子的胸腺生成作用。IL-7 R α链是TSLP和IL-7共享的链。在另一项研究中，我们产生了IL-7 Ra转基因小鼠，其用于显示IL-7 Ra的组成型表达不足以支持单核细胞增生李斯特菌感染期间淋巴细胞的扩增增加或防止淋巴细胞的收缩。 总体而言，这些研究有助于提高我们对GC家族细胞因子和TSLP信号传导的理解。这些发现阐明了与免疫缺陷、过敏、自身免疫和癌症以及T细胞和B细胞活动的基本控制相关的分子机制。