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: 9572286
• 负责人: Warren J Leonard
• 金额: $ 50.1万
• 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/9572286
• 关键词: 4T1; Acids; Allergic; Allergic inflammation; Asthma; 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; Dendritic Cells; Development; Disease; Event; Family; Genes; Growth; Human; IL7R gene; Immune response; Immunity; Inflammasome; Inflammation; Interleukin 2 Receptor; Interleukin 2 Receptor Gamma; Interleukin 7 Receptor; Interleukin-10; Interleukin-13; Interleukin-15; Interleukin-2; Interleukin-4; Interleukin-7; Interleukin-9; JAK1 gene; JAK2 gene; Link; Literature; Lung; Lung Inflammation; Malignant Neoplasms; Mediating; Molecular; Mus; Mutate; Mutation; Neoplasm Metastasis; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Play; Production; Pyroglyphidae; Reactive Oxygen Species; Regulatory T-Lymphocyte; Reporting; Role; Signal Transduction; Skin; Solid Neoplasm; Stat5 protein; Streptococcus pyogenes; System; T-Lymphocyte; TSLP gene; Therapeutic; Time; Work; X-Linked Severe Combined Immunodeficiency; autocrine; base; cytokine; human disease; immune system function; killings; liver injury; malignant breast neoplasm; methicillin resistant Staphylococcus aureus; mouse model; neoplastic; neutrophil; novel; 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 IL7R. We 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 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. 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 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; 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. In the past year, we have continued to work on aspects of the biology of TSLP, making substantial progress on novel actions of this cytokine. In related work, we made major contributions to a study showing that T helper 1 immunity requires complement-driven NLRP3 inflammasome activity. In the past year, in a collaborative study that skin-derived TSLP systemically expands regulatory T cells. Moreover, we reported that TSLP also 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. These studies revealed an unappreciated action of TSLP and moreover provide the first link between a type I cytokine and complement activation. Thus, our findings not only have elucidated new biology but also have potential therapeutic implications implications. 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.

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IL 7 R。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。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，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。在过去的一年中，我们继续致力于TSLP生物学方面的研究，在这种细胞因子的新作用方面取得了实质性进展。在相关工作中，我们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。在过去的一年中，在一项合作研究中，皮肤来源的TSLP系统性地扩增了调节性T细胞。此外，我们还报道了TSLP还可以促进嗜中性粒细胞依赖性杀伤耐甲氧西林金黄色葡萄球菌和化脓性链球菌，并且它通过依赖于活性氧和补体的途径介导这种杀伤。这些研究揭示了TSLP的未被重视的作用，而且提供了I型细胞因子和补体激活之间的第一个联系。因此，我们的发现不仅阐明了新的生物学，而且具有潜在的治疗意义。 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。