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: 10929103
• 负责人: Warren J Leonard
• 金额: $ 61.58万
• 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/10929103
• 关键词: 4T1; Acids; Acute; Affect; Allergic; Allergic Disease; Allergic inflammation; Antibody Formation; Antiviral Response; Asthma; Atopic Dermatitis; B-Lymphocytes; Biological Models; Biology; Brain; Breast; Breast Melanoma; CD27 Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell physiology; Cloning; Collaborations; Complement; Complement Activation; Cytokine Activation; Cytokine Receptors; Data; Dendritic Cells; Development; Disease; Epithelial Cells; Epithelium; Event; Family; Genes; Goals; Growth; Hair follicle structure; Human; IL7 gene; IL7R gene; Immune; Immune response; Immunity; Immunization; Immunologic Deficiency Syndromes; Inflammasome; Inflammation; Influenza; Interleukin 2 Receptor; Interleukin 2 Receptor Gamma; Interleukin-10; Interleukin-13; Interleukin-15; Interleukin-2; Interleukin-4; Interleukin-9; JAK1 gene; JAK2 gene; Link; Literature; Lung; Lymphocytic choriomeningitis virus; Lymphoid Cell; Maintenance; Malignant Neoplasms; Manuscripts; Mediating; Memory; Molecular; Mus; Mutate; Mutation; Names; Natural Killer Cells; Neoplasm Metastasis; Papain; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Phosphotransferases; Physiology; Play; Production; Proliferating; Publishing; Pulmonary Inflammation; Pyroglyphidae; Reactive Oxygen Species; Regulatory T-Lymphocyte; Reporting; Retinoids; Role; Sebaceous Glands; Secondary to; Signal Transduction; Skin; Solid Neoplasm; Stat5 protein; Streptococcus pyogenes; Surface; Symbiosis; System; T cell response; T-Cell Development; T-Lymphocyte; TSLP gene; Th2 Cells; Therapeutic; Time; Virus Diseases; Work; X-Linked Severe Combined Immunodeficiency; aluminum sulfate; asthma model; autocrine; autosome; cytokine; drug induced liver injury; helminth infection; human disease; immune system function; interleukin-21; malignant breast neoplasm; methicillin resistant Staphylococcus aureus; microbial; mouse model; neoplastic; neutrophil; programs; receptor; response; 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. As detailed below, TSLP is related to IL-7. 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, in contrast 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 in a 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 contributed 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. Finally, we previously 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. We also previously investigated the role of TSLP in primary and recall CD8 T cell antiviral response. As noted above, TSLP acts directly on CD4+ T cells and dendritic cells to promote allergic disease (e.g., asthma and atopic dermatitis). However, the role for TSLP in CD8+ T-cell primary responses had been controversial, and its role in memory CD8+ T cell responses to secondary viral infection has been unknown. We thus had investigated the role of TSLP in primary and recall responses in mice using influenza and lymphocyte choriomeningitis virus (LCMV). TSLP limited the primary CD8+ T-cell response to influenza but did not affect T cell function nor significantly alter the number of memory CD8+ T cells. However, this cytokine inhibited memory CD8+ T-cell responses to secondary viral infection with either influenza or acute LCMV infection. Thus, TSLP affects recall CD8+ T-cell responses following viral infection. These observations may have translational implications. In the current year, we are making use of new genetically altered mice we generated to further explore the biology of TSLP in normal and disease states. Considerable new data have been generated with a manuscript under review as well as published abstracts. We also reported that crosstalk between ILC2s and Th2 cells varies in different mouse models. By generating mice deficient in either ILC2s or Th2 cells, we found that IL-33-mediated ILC2 activation promoted the Th2 cell response to papain, whereas the Th2 response to OVA/alum immunization is dependent on TSLP but independent of ILC2s. During helminth infection, Th2 cells express IL-25, IL-33, and TSLP. 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，该实验室于 1986 年共同发现了 IL-2Rb，随后于 1993 年报告称 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），随后于 1995 年发现 gc 相关激酶 Jak3 的突变导致常染色体隐性遗传性 SCID 与 XSCID 无法区分，1998 年 T-B+NK+ SCID 是由 IL7R 基因突变引起的。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。如下文详述，TSLP 与 IL-7 相关。 我们之前与麻省理工学院的 Harvey Lodish 实验室合作，报道了本报告主题的胸腺基质淋巴细胞生成素 (TSLP) 受体的克隆，并表明 TSLP 的功能受体是 TSLPR + IL7R。然后，我们证明，与文献中的报道相反，TSLP 不仅通过树突状细胞发挥主要作用，而且还通过人类和小鼠的 CD4+ T 细胞发挥主要作用，TSLP 还通过 CD8+ T 细胞上的受体发出信号，并与 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。我们还表明，虽然 TSLP 和 IL-7 共享 IL-7R，但它们的功能是不同的，并且 TSLP 促进 CD4 T 细胞发育，而 IL-7 与 IL-15 一样，有利于 CD8 T 细胞发育。我们之前还表明，TSLP 在哮喘小鼠模型中过敏性肺部炎症的发展中发挥着关键作用，而 CD4+ T 细胞对于这些作用至关重要。此外，我们报道了 TSLP 通过 JAK1 和 JAK2 而不是通过 Tek 家族激酶发出信号，如文献中所建议的那样，介导人类和小鼠 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。我们还表明，JAK1 通过 TSLPR 与 IL7R 和 JAK2 相关，阐明了 TSLP 信号传导并提供了第一个使用 JAK1 和 JAK2 组合介导 STAT5 激活的细胞因子示例。我们发现，已知对 TSLP 作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，这表明它们对这种细胞因子的反应可能存在自分泌机制。此外，我们与 Arya Biragyn 一起证明，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，产生 IL-10 和 IL-13；与 N. Hirasawa 合作，壬酸可诱导 TSLP 并加剧小鼠过敏性炎症； C. Ellison 认为，功能性 TSLP 受体的缺乏会减轻 Th2 极化以及 4T1 原发性乳腺肿瘤的形成和生长，但对肺和脑中的肿瘤数量有不同的影响。此外，我们之前与 L. Pohl 合作证明了 TSLP 和 IL-4 介导小鼠药物性肝损伤的发病机制。我们还参与了一项研究，表明 T 辅助细胞 1 免疫需要补体驱动的 NLRP3 炎性体活性，并参与了皮肤源性 TSLP 系统性扩展调节性 T 细胞的合作研究。此外，我们之前报道过，TSLP 可以促进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，揭示了 TSLP 的未受重视的作用，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 合作，报道了全反式视黄酸可以通过诱导 TSLP 来增强抗体产生，并与 Y. Rochman 和 H. Singh 合作进行研究，发现 CD4+ T 细胞中的 TSLP 信号传导可以编程致病性 Th2 状态。最后，我们之前与 K. Nagao 合作进行的一项研究表明，皮肤固有淋巴细胞 (ILC) 存在空间分区，并且位于皮脂腺附近毛囊中的 RORgt+ ILC 子集对皮脂腺进行调节。这些 ILC 的持续存在需要 IL-7 和 TSLP。因此，上皮源性细胞因子对于维持调节微生物共生的皮肤驻留 ILC 非常重要，数据表明调节屏障表面的免疫-上皮细胞关系。 我们之前还研究了 TSLP 在初级和回忆 CD8 T 细胞抗病毒反应中的作用。如上所述，TSLP 直接作用于 CD4+ T 细胞和树突状细胞，促进过敏性疾病（例如哮喘和特应性皮炎）。然而，TSLP 在 CD8+ T 细胞初次反应中的作用一直存在争议，并且其在记忆 CD8+ T 细胞对继发病毒感染反应中的作用尚不清楚。因此，我们使用流感病毒和淋巴细胞脉络膜脑膜炎病毒（LCMV）研究了 TSLP 在小鼠初级反应和回忆反应中的作用。 TSLP 限制了 CD8+ T 细胞对流感的初级反应，但不影响 T 细胞功能，也不显着改变记忆 CD8+ T 细胞的数量。然而，这种细胞因子抑制记忆 CD8+ T 细胞对流感或急性 LCMV 感染继发病毒感染的反应。因此，TSLP 会影响病毒感染后的 CD8+ T 细胞反应。这些观察结果可能具有转化意义。 今年，我们正在利用我们培育的新型基因改造小鼠来进一步探索 TSLP 在正常和疾病状态下的生物学特性。正在审查的手稿以及已发表的摘要已经生成了大量新数据。我们还报道了不同小鼠模型中 ILC2 和 Th2 细胞之间的串扰有所不同。通过生成 ILC2 或 Th2 细胞缺陷的小鼠，我们发现 IL-33 介导的 ILC2 激活促进了 Th2 细胞对木瓜蛋白酶的反应，而 Th2 对 OVA/明矾免疫的反应依赖于 TSLP，但独立于 ILC2。蠕虫感染期间，Th2 细胞表达 IL-25、IL-33 和 TSLP。 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。

项目成果

Role of thymic stromal lymphopoietin in allergy and beyond.

• DOI: 10.1038/s41577-022-00735-y
• 发表时间: 2023-01
• 期刊: Nature reviews. Immunology

TSLP-targeting therapy: Beyond allergy?

• DOI: 10.1002/ctm2.1241
• 发表时间: 2023-05
• 期刊: Clinical and translational medicine
• 影响因子: 10.6

The role of thymic stromal lymphopoietin in CD8+ T cell homeostasis.

• DOI: 10.4049/jimmunol.181.11.7699
• 发表时间: 2008-12-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Rochman Y;Leonard WJ
• 通讯作者: Leonard WJ

Thymic stromal lymphopoietin is produced by dendritic cells.

胸腺基质淋巴细胞素由树突状细胞产生。

• DOI: 10.4049/jimmunol.1100355
• 发表时间: 2011-08-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Kashyap M;Rochman Y;Spolski R;Samsel L;Leonard WJ
• 通讯作者: Leonard WJ

Thymic stromal lymphopoietin is a key mediator of breast cancer progression.

• DOI: 10.4049/jimmunol.1100463
• 发表时间: 2011-05-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Olkhanud PB;Rochman Y;Bodogai M;Malchinkhuu E;Wejksza K;Xu M;Gress RE;Hesdorffer C;Leonard WJ;Biragyn A
• 通讯作者: Biragyn A