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: 8939805
• 负责人: Warren J Leonard
• 金额: $ 42.54万
• 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/8939805
• 关键词: Acids; Allergic; Allergic inflammation; Asthma; Autoimmunity; Biological Models; Biology; Brain; Breast; Breast Melanoma; CD27 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cloning; Collaborations; Cytokine Receptors; Dendritic Cells; Development; Event; Family; Genes; Growth; Homeostasis; Human; Hypersensitivity; IL7R gene; Immune response; Immune system; Immunologic Deficiency Syndromes; Interleukin 2 Receptor Gamma; Interleukin-10; Interleukin-13; Interleukin-15; Interleukin-2; Interleukin-4; Interleukin-7; Interleukin-9; JAK1 gene; JAK2 gene; Literature; Lung; Lung Inflammation; Lymphoid; Malignant Neoplasms; Mediating; Molecular; Mus; Mutate; Mutation; Neoplasm Metastasis; Pathogenesis; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Play; Production; Pyroglyphidae; Regulatory T-Lymphocyte; Reporting; Role; STAT5A gene; Signal Transduction; Solid Neoplasm; System; T-Cell Development; T-Lymphocyte; Time; Work; X-Linked Severe Combined Immunodeficiency; autocrine; base; cytokine; human TSLP protein; human disease; liver injury; malignant breast neoplasm; mouse model; neoplastic; receptor; tumor

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 collaboration with Harvey Lodish's lab at MIT, we previously reported the cloning of the receptor for thymic stromal lymphopoietin (TSLP). The functional receptor for TSLP is TSLPR plus gc. We then demonstrated that TSLP, counter to the sense of the literature, exerted major actions via CD4+ T cells in both humans and mice, and previously showed with Scott Durum 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. We also showed that although both TSLP and IL-7 share the IL-7 receptor alpha chain, the functions of TSLP and IL-7 are distinctive. We showed that TSLP promotes CD4 T cell development whereas IL-7 and IL-15 favor CD8 T cell development. We also previously showed that TSLP plays a critical role in the development of allergic lung inflammation mouse model of asthma, and that CD4+ T cells are essential for those actions. Previously, we demonstrated and reported that TSLP signals via JAK1 and JAK2 rather than through a Tek family kinase, as had been suggested in the literature, to mediate the activation of STAT5 in both human and mouse T cells, and that STAT5 mediated TSLP-induced survival and proliferation of CD4+ T cells. We also previously showed that JAK1 associates with IL7R and JAK2 with TSLPR, clarifying the basis for TSLP signaling and providing the first example of a cytokine using the combination of JAK1 and JAK2 to mediate the activation of STAT5. We also showed that dendritic cells, which were known to respond to TSLP, unexpectedly produce TSLP, including after challenge with house dust mite extract, suggesting a possibly autocrine mechanism for their responsiveness to this cytokine. Furthermore, we previously showed with Arya Biragyn that TSLP produced by human and mouse solid tumors contributes to progression and metastasis in breast cancer and melanoma model systems and that the cancer-romoting action of TSLP is mediated via its action on T cells, with the production of IL-10 and IL-13. In the current year, we reported with N. Hirasawa that nonanoic acid can induce TSLP and exacerbate allergic inflammation in mice and with C. Ellison that the lack of functional TSLP receptors mitigates Th2 polarization and the establishment and growth of 4T1 primary breast tmors but has different effects on tumor quantities in the lung and brain. Moreover, with L. Pohl, we demonstrated that TSLP and IL-4 mediate the pathogenesis of drug-induced liver injury in mice. We have also continued to work on aspects of the biology of TSLP. Overall, these studies have increased 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 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。 在麻省理工学院的Harvey Lodish实验室的合作下，我们先前报道了胸腺基质淋巴细胞生成素（TSLP）受体的克隆。TSLP的功能性受体是TSLPR加gc。然后，我们证明了TSLP，与文献的意义相反，在人类和小鼠中通过CD 4 + T细胞发挥主要作用，并且先前与Scott Durum一起表明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，并且TSLP还通过CD 8 + T细胞上的受体发出信号。我们还表明，虽然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细胞发育，而IL-7和IL-15有利于CD 8 T细胞发育。我们以前也表明TSLP在哮喘变应性肺炎小鼠模型的发展中起着关键作用，并且CD 4 + T细胞对于这些作用至关重要。以前，我们证明并报道TSLP信号通过JAK 1和JAK 2，而不是通过Tek家族激酶，如文献中所建议的，介导人和小鼠T细胞中STAT 5的活化，并且STAT 5介导TSLP诱导的CD 4 + T细胞的存活和增殖。我们之前还表明JAK 1与IL 7 R和JAK 2与TSLPR相关，阐明了TSLP信号传导的基础，并提供了使用JAK 1和JAK 2组合介导STAT 5激活的细胞因子的第一个例子。我们还表明，树突状细胞，这是已知的响应TSLP，意外地产生TSLP，包括后的挑战与屋尘螨提取物，这表明一个可能的自分泌机制，为他们的反应，这种细胞因子。此外，我们先前与Arya Biragyn一起表明，人和小鼠实体瘤产生的TSLP有助于乳腺癌和黑色素瘤模型系统的进展和转移，并且TSLP的促癌作用是通过其对T细胞的作用介导的，产生IL-10和IL-13。本年度，我们与N. Hirasawa认为壬酸可诱导TSLP并加重小鼠过敏性炎症反应，而C. Ellison认为，功能性TSLP受体的缺乏减轻了Th 2极化以及4 T1原发性乳腺肿瘤的建立和生长，但对肺和脑中的肿瘤数量具有不同的影响。此外，与L. Pohl的研究表明，TSLP和IL-4介导了小鼠药物性肝损伤的发病机制。我们还继续研究TSLP的生物学方面。 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淋巴稳态相关的分子机制。