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: 8557960
• 负责人: Warren J Leonard
• 金额: $ 89.78万
• 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/8557960
• 关键词: Allergic; Allergic inflammation; Asthma; Autoimmunity; Biological Models; Biology; Breast Melanoma; CD27 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Cloning; Collaborations; Cytokine Receptors; Decidua; Dendritic Cells; Development; Event; Family; Genes; 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; Japan; Literature; Lung Inflammation; Lymphoid; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Mutate; Mutation; Natural Killer Cells; Neoplasm Metastasis; Phenotype; Phosphotransferases; Picryl Chloride; Play; Pregnancy; 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; Xylene; autocrine; base; cytokine; graft vs host disease; human TSLP protein; human disease; implantation; keratinocyte growth factor; malignant breast neoplasm; 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 collaboration with Harvey Lodish's lab at MIT, we previously reported the cloning of the receptor for thymic stromal lymphopoietin (TSLP). 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. 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 development of allergic lung inflammation mouse model of asthma, and that CD4+ T cells are essential for its action in that model. In the previous year, 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 primary T cells, and that STAT5 mediated TSLP-induced survival and proliferation of CD4+ T cells. We showed that JAK1 associates with IL7R and JAK2 with TSLPR, thus clarifying the basis for TSLP signaling and provided the first example of a cytokine using the combination of JAK1 and JAK2 to mediate the activation of STAT5. We also previously demonstrated 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. With Arya Biragyn, we also demonstrated 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 past year, with N. Hirasawa in Japan, we reported that TSLP responsiveness was required for palifermin-mediated protection from graft versus host disease and that moreover, TSLP was induced by xylene and associated with exacerbation of picryl chloride-induced allergic inflammation. In another study, with B. Anne Croy in Toronto, we reported findings related to the timing of expression of IL-7Ra expression by mouse uterine NK cells. We found that cells expressing IL-7Ra were found in mouse decidua and found that it was expressed in a uterine NK subset in gd 10.5 decidua, and uterine NK cells also expressed TSLPR. Neither IL-7 nor TSLP was required for the development of uterine NK cells during normal pregnancy, but each cytokine had functional impact on uterine NK cells in separate regions of implantation. We also have continued our studies of TSLP related to allergic inflammation. 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 受体和相关细胞因子受体系统正在研究中，以阐明正常、肿瘤和免疫缺陷状态下的 T 细胞免疫反应。 T 细胞被抗原激活后，T 细胞免疫反应的强度和持续时间取决于产生的 IL-2 量、表达的受体水平以及每个事件的时间进程。 IL-2受体包含3条链：IL-2Ra、IL-2Rb和gc。 Leonard 博士于 1984 年克隆了 IL-2Ra，我们于 1986 年发现了 IL-2Rb，并于 1993 年报道了 gc 链突变导致人类 X 连锁严重联合免疫缺陷（XSCID，具有 T-B+NK- 表型）。我们于 1995 年报道，gc 相关激酶 Jak3 的突变导致与 XSCID 无法区分的常染色体隐性 SCID，并于 1998 年报道 T-B+NK+ SCID 由 IL7R 基因突变引起。根据我们实验室和其他实验室的工作，gc 先前被证明由 IL-2、IL-4、IL-7、IL-9、IL-15 和 IL-21 受体共享。 我们之前与麻省理工学院 Harvey Lodish 实验室合作，报道了胸腺基质淋巴细胞生成素 (TSLP) 受体的克隆。然后，我们证明了 TSLP（与文献的意义相反）通过 CD4+ T 细胞在人类和小鼠中发挥主要作用，并且之前与 Scott Durum 一起证明 TSLP 和 IL-7（共享 IL-7Ra 作为受体成分）都驱动调节性 T 细胞的发育，并且 TSLP 还通过 CD8+ T 细胞上的受体发出信号。 TSLPR 与 gc 最相关，我们发现虽然 TSLP 和 IL-7 共享 IL-7 受体 α 链，但 TSLP 和 IL-7 的功能是不同的。我们表明，TSLP 促进 CD4 T 细胞发育，而同样共享 gc 的 IL-7 和 IL-15 有利于 CD8 T 细胞发育，并且 TSLP 在过敏性肺部炎症哮喘小鼠模型的发育中起着关键作用，并且 CD4+ T 细胞对其在该模型中的作用至关重要。去年，我们证明并报道了 TSLP 信号通过 JAK1 和 JAK2 而不是通过 Tek 家族激酶发出信号，正如文献中所建议的那样介导人类和小鼠原代 T 细胞中 STAT5 的激活，并且 STAT5 介导 TSLP 诱导的 CD4+ T 细胞的存活和增殖。我们发现 JAK1 与 IL7R 相关，JAK2 与 TSLPR 相关，从而阐明了 TSLP 信号转导的基础，并提供了细胞因子使用 JAK1 和 JAK2 组合介导 STAT5 激活的第一个例子。我们之前还证明，已知对 TSLP 做出反应的树突状细胞意外地产生 TSLP，包括在用屋尘螨提取物攻击后，这表明树突状细胞对这种细胞因子的反应可能是自分泌机制。通过 Arya Biragyn，我们还证明了人类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 的癌症促进作用是通过其对 T 细胞的作用介导的，并产生 IL-10 和 IL-13。 去年，我们与日本的 N. Hirasawa 一起报道了 TSLP 反应性是 palifermin 介导的移植物抗宿主病保护所必需的，此外，TSLP 是由二甲苯诱导的，并且与苦酰氯诱导的过敏性炎症的恶化有关。在多伦多的 B. Anne Croy 的另一项研究中，我们报告了与小鼠子宫 NK 细胞表达 IL-7Ra 的时间相关的发现。我们发现在小鼠蜕膜中发现了表达IL-7Ra的细胞，并发现其在gd 10.5蜕膜中的子宫NK亚群中表达，并且子宫NK细胞也表达TSLPR。正常妊娠期间子宫 NK 细胞的发育不需要 IL-7 和 TSLP，但每种细胞因子对不同植入区域的子宫 NK 细胞都有功能影响。我们还继续研究与过敏性炎症相关的 TSLP。 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。