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: 10262670
• 负责人: Warren J Leonard
• 金额: $ 53.88万
• 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/10262670
• 关键词: 4T1; Acids; Allergic; Allergic inflammation; Antibody Formation; B-Lymphocytes; Biological Models; Biology; Brain; Breast; Breast Melanoma; CD27 Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cloning; Collaborations; Complement; Complement Activation; Cytokine Activation; Cytokine Receptors; Data; Dendritic Cells; Development; Disease; Epithelial; Epithelial Cells; Epithelium; Event; Family; Genes; Goals; Growth; Hair follicle structure; Human; IL7R gene; Immune; Immune response; Immunity; Inflammasome; Inflammation; Interleukin 2 Receptor; Interleukin 2 Receptor Gamma; Interleukin-10; Interleukin-13; Interleukin-15; Interleukin-2; Interleukin-4; Interleukin-7; Interleukin-9; JAK1 gene; JAK2 gene; Link; Literature; Lung; Lung Inflammation; Lymphoid Cell; Maintenance; Malignant Neoplasms; Manuscripts; Mediating; Molecular; Mus; Mutate; Mutation; Natural Killer Cells; Neoplasm Metastasis; Pathogenesis; Pathogenicity; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Physiology; Play; Production; Pyroglyphidae; Reactive Oxygen Species; Regulatory T-Lymphocyte; Reporting; Retinoids; Role; Sebaceous Glands; Signal Transduction; Skin; Solid Neoplasm; Stat5 protein; Streptococcus pyogenes; Surface; Symbiosis; System; T-Cell Development; T-Lymphocyte; TSLP gene; Therapeutic; Time; Work; X-Linked Severe Combined Immunodeficiency; asthma model; autocrine; base; cytokine; human disease; immune system function; liver injury; malignant breast neoplasm; methicillin resistant Staphylococcus aureus; microbial; mouse model; neoplastic; neutrophil; programs; receptor; tumor

The IL-2 receptor and related cytokine receptor systems are being studied to clarify the 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, the lab co-discovered IL-2Rb in 1986, and then 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 and then in 1995 discovered 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 topic of this report, and showed that the functional receptor for TSLP is TSLPR + IL7R. We then demonstrated that TSLP, counter to reports in the literature, exerted major actions not only via dendritic cells but also via CD4+ T cells in both humans and mice, that TSLP also signals via receptors on CD8+ T cells, and 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. We also showed that although TSLP and IL-7 share IL-7R, their functions are distinctive, and that TSLP promotes CD4 T cell development whereas IL-7, like IL-15, favors 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. Moreover, we 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 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 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 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; 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 previously demonstrated that TSLP and IL-4 mediate the pathogenesis of drug-induced liver injury in mice. We also made major contributions to a study showing that T helper 1 immunity requires complement-driven NLRP3 inflammasome activity and contributed to a collaborative study that skin-derived TSLP systemically expands regulatory T cells. Moreover, we previously reported that TSLP can promote neutrophil-dependent killing of methicillin-resistant Staphylococcus aureus and Streptococcus pyogenes and that it mediates such killing via pathway(s)dependent on reactive oxygen species and complement, revealing an unappreciated action of TSLP and providing the first link between a type I cytokine and complement activation. We also contributed to a collaboration with N. Hirasawa that reported that all-trans retinoid acid can enhance antibody production by inducing TSLP and to a study with Y. Rochman and H. Singh that TSLP signaling in CD4+ T cells can program a pathogenic Th2 state. Last year, we contributed to a study with K. Nagao showing that there is spatial compartmentalization of skin-resident innate lymphoid cells (ILCs) and modulation of sebaceous glands by a subset of RORgt+ ILCs that are located in hair follicles adjacent to sebaceous glands. The persistence of these ILCs required both IL-7 and TSLP. Thus, epithelial-derived cytokines are important for the maintenance of skin-resident ILCs that regulate microbial commensalism, with the data indicating an immune-epithelial cell relationship for regulating the barrier surface. In the current year, we have continued studies to elucidate the biology of TSLP and a manuscript has been submitted. Overall, these studies have increased our understanding of signaling by gc family cytokines and TSLP, clarifying molecular mechanisms that are relevant to inflammation and disease-- both elucidating new biology and also having potential therapeutic implications.

正在研究IL-2受体和相关细胞因子受体系统，以阐明正常、肿瘤和免疫缺陷状态下的免疫应答。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，该实验室于1986年共同发现了IL-2 Rb，然后于1993年报告了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），然后在1995年发现GC相关激酶Jak 3，导致与XSCID难以区分的常染色体隐性形式的SCID，并且在1998年，T-B+NK+ SCID由IL 7 R基因中的突变引起。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。 与Harvey Lodish在MIT的实验室合作，我们先前报道了胸腺基质淋巴细胞生成素（TSLP）受体的克隆，这是本报告的主题，并表明TSLP的功能性受体是TSLPR + IL 7 R。然后，我们证明了TSLP，与文献中的报道相反，不仅通过树突状细胞，而且还通过人类和小鼠中的CD 4 + T细胞发挥主要作用，TSLP还通过CD 8 + T细胞上的受体发出信号，并与Scott Durum一起显示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。我们还表明，虽然TSLP和IL-7共享IL-7 R，但它们的功能是不同的，TSLP促进CD 4 T细胞发育，而IL-7，如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。此外，我们报道了TSLP信号通过JAK 1和JAK 2而不是如文献中所建议的通过Tek家族激酶来介导人和小鼠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。我们还表明JAK 1与IL 7 R缔合，JAK 2与TSLPR缔合，阐明了TSLP信号传导的基础，并提供了使用JAK 1和JAK 2的组合介导STAT 5活化的细胞因子的第一个实例。我们发现，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，他们对这种细胞因子的反应。此外，我们与Arya Biragyn一起证明，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，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;与N. Hirasawa认为壬酸可诱导小鼠TSLP并加重过敏性炎症; 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，我们之前证明TSLP和IL-4介导了小鼠药物性肝损伤的发病机制。我们还对一项研究做出了重大贡献，该研究表明T辅助细胞1免疫需要补体驱动的NLRP 3炎性体活性，并对皮肤来源的TSLP系统性扩增调节性T细胞的合作研究做出了贡献。此外，我们先前报道了TSLP可以促进对耐甲氧西林金黄色葡萄球菌和化脓性链球菌的嗜中性粒细胞依赖性杀伤，并且它通过依赖于活性氧和补体的途径介导这种杀伤，揭示了TSLP的未被认识的作用，并提供了I型细胞因子和补体激活之间的第一个联系。我们还与N. Hirasawa等报道，全反式维甲酸可以通过诱导TSLP来增强抗体的产生。Rochman和H. Singh认为，CD 4 + T细胞中的TSLP信号传导可以编程致病性Th 2状态。去年，我们与K. Nagao的研究表明，存在皮肤驻留的先天淋巴样细胞（ILC）的空间区室化和通过位于毛囊中邻近皮脂腺的RORgt+ ILC的子集对皮脂腺的调节。这些ILC的持续存在需要IL-7和TSLP。因此，上皮衍生的细胞因子对于维持调节微生物代谢的皮肤驻留ILC是重要的，数据表明用于调节屏障表面的免疫-上皮细胞关系。 在本年度，我们继续研究，以阐明TSLP的生物学和手稿已提交。 总的来说，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，阐明了与炎症和疾病相关的分子机制-既阐明了新的生物学，也具有潜在的治疗意义。