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: 7969132
• 负责人: Warren J Leonard
• 金额: $ 88.01万
• 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/7969132
• 关键词: Autoimmunity; BCL2 gene; Binding Proteins; Biological Models; Biology; CD27 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cell Survival; Cells; Cloning; Collaborations; Cytokine Receptors; Data; Dendritic Cells; Development; Event; Exhibits; Extrinsic asthma; Family; Genes; Homeostasis; Human; Hypersensitivity; IL7R gene; Immune response; Immune system; Immunologic Deficiency Syndromes; In Vitro; Interleukin 2 Receptor; Interleukin 2 Receptor Gamma; Interleukin 7 Receptor; Interleukin-15; Interleukin-2; Interleukin-4; Interleukin-7; Interleukin-9; Literature; Lymphoid; Malignant Neoplasms; Molecular; Mus; Mutate; Mutation; Phenotype; Phosphotransferases; Play; Population; Proto-Oncogene Proteins c-akt; Reporting; Role; STAT5A gene; Signal Transduction; System; T-Cell Development; T-Lymphocyte; Time; Work; X-Linked Severe Combined Immunodeficiency; base; cytokine; human TSLP protein; human disease; in vivo; mast cell; mouse model; neoplastic; 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 reported 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. Having preveiously demonstrated that TSLP receptors are expressed on mouse and human CD4+ T cells, we importantly demonstrated and reported that they are also expressed on CD8+ T cells. Thus, in addition to expression of TSLP receptors on dendritic cells and mast cells, our data reveal the presence of TSLP receptors on these two major populations of T cells. We also showed that TSLP could activate STAT5 and AKT as well as induce BCL2 expression in these cells. Corresponding, TSLP also promoted CD8+ T cell survival in vitro and in vivo, and could maintain these cells even in the absence of IL-7, revealing important roles for TSLP in lymphoid homeostasis. 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.

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，我们报道了TSLP和IL-7，它们共享IL-7 Ra作为受体组分，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表现出部分重叠的作用。 在成功证明TSLP受体在小鼠和人CD 4 + T细胞上表达后，我们重要地证明并报道了它们也在CD 8 + T细胞上表达。因此，除了在树突状细胞和肥大细胞上表达TSLP受体外，我们的数据还揭示了在这两种主要的T细胞群体上存在TSLP受体。我们还发现TSLP可以激活这些细胞中的STAT 5和AKT，并诱导BCL 2表达。相应地，TSLP还在体外和体内促进CD 8 + T细胞的存活，并且即使在没有IL-7的情况下也可以维持这些细胞，揭示了TSLP在淋巴稳态中的重要作用。 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。