IL-2 Family Cytokines and their Receptors--Biology of the IL-7/TSLP Systems

正在研究IL-2受体和相关的细胞因子受体系统，以阐明正常、肿瘤和免疫缺陷状态下的免疫反应。在抗原激活T细胞后，T细胞免疫反应的大小和持续时间取决于产生的IL-2的数量、受体的表达水平和每个事件的时间进程。IL-2受体含有IL-2Ra、IL-2Rb和GC三条链。伦纳德博士在1984年克隆了IL-2Ra，实验室在1986年共同发现了IL-2Rb，然后在1993年报告了GC链的突变导致了人类的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相关的激酶JAK3的突变导致了一种与XSCID难以区分的常染色体隐性形式的SCID，1998年T-B+NK+SCID是由IL7R基因的突变引起的。根据我们实验室和其他实验室的工作，先前发现GC由IL-2、IL-4、IL-7、IL-9、IL-15和IL-21的受体共享。 在与哈维·洛迪什在麻省理工学院的实验室合作中，我们之前报道了胸腺基质淋巴生成素受体(TSLP)的克隆，并表明TSLP的功能性受体是TSLPR+IL7R。然后，我们证明了TSLP，与文献报道相反，在人类和小鼠中不仅通过树突状细胞发挥主要作用，而且通过CD4+T细胞发挥主要作用，TSLP还通过CD8+T细胞上的受体传递信号，并与Scott Durum证明TSLP和IL-7作为受体成分共享IL-7ra，都驱动调节性T细胞的发育。我们还发现，尽管TSLP和IL-7具有相同的IL-7R，但它们的功能是不同的，TSLP促进CD4T细胞的发育，而IL-7和IL-15一样，促进CD8T细胞的发育。我们之前还发现，TSLP在哮喘小鼠过敏性肺部炎症模型的发展中起着关键作用，而CD4+T细胞对这些作用是必不可少的。此外，我们报道了TSLP信号通过JAK1和JAK2而不是文献中所建议的通过TEK家族激酶来介导STAT5在人和小鼠T细胞中的激活，以及STAT5介导TSLP诱导的CD4+T细胞的生存和增殖。我们还证明了JAK1与IL7R和JAK2与TSLPR的联系，阐明了TSLP信号转导的基础，并提供了第一个使用JAK1和JAK2的组合来介导STAT5激活的细胞因子的例子。我们发现，已知对TSLP有反应的树突状细胞出人意料地产生TSLP，包括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是自分泌机制。此外，我们与Arya Biragyn一起证明了由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的癌症转移作用是通过其对T细胞的作用而介导的，其产生IL-10和IL-13；与N.Hirasawa共同研究表明，壬酸可诱导TSLP并加剧小鼠的过敏性炎症；与C.Ellison共同研究表明，功能性TSLP受体的缺乏缓解了Th2极化，导致4T1原发乳腺癌的建立和生长，但对肺和脑中的肿瘤数量有不同的影响。此外，我们以前与L.Pohl一起证明了TSLP和IL-4介导了小鼠药物性肝损伤的发病机制。我们还为一项研究做出了重大贡献，该研究表明T辅助1免疫需要补体驱动的NLRP3炎症体活动，并参与了一项合作研究，即皮肤来源的TSLP系统地扩大了调节性T细胞。此外，我们先前报道，TSLP可以促进中性粒细胞对甲氧西林耐药金黄色葡萄球菌和化脓性链球菌的杀伤，并通过依赖于活性氧和补体的途径(S)介导这种杀伤，揭示了TSLP未被认识的作用，并在I型细胞因子和补体激活之间提供了第一个联系。我们还与N.Hirasawa合作，报道了全反式维甲酸可以通过诱导TSLP来增强抗体产生，以及与Y.Rochman和H.Singh合作的一项研究，即CD4+T细胞中的TSLP信号可以编程致病的Th2状态。在这一年，我们与K.Nagao共同参与的一项研究表明，皮肤固有淋巴样细胞(ILCs)存在空间区隔，皮脂腺受到位于皮脂腺附近毛囊中的RORgt+ILCs的调节。这些ILC的持久性需要IL-7和TSLP。因此，上皮来源的细胞因子对于维持调节微生物共生的皮肤驻留的ILCs是重要的，数据表明调节屏障表面的免疫-上皮细胞关系。我们还继续研究阐明TSLP的生物学，并开发了与TSLP相关的新的基因敲除小鼠模型。 总体而言，这些研究增加了我们对GC家族细胞因子和TSLP信号传递的理解，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。

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. In the current 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. We also have continued studies to elucidate the biology of TSLP and developed new TSLP-related knockout mouse models. 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.