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T细胞免疫反应。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。1984年伦纳德博士克隆了IL-2Ra，1986年我们发现了IL-2Rb，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)。我们在1995年报道了GC相关激酶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，并在1998年报道了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，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(TSLP)受体的克隆。然后，我们证明了TSLP，与文献中的意义相反，在人类和小鼠中通过CD4+T细胞发挥主要作用，之前与Scott Durum一起证明TSLP和IL-7作为受体成分共享IL-7Ra，两者都驱动调节性T细胞的发育，TSLP也通过CD8+T细胞上的受体发出信号。TSLPR与GC关系最密切，我们发现虽然TSLP和IL-7都有IL-7受体α链，但TSLP和IL-7的功能不同。我们发现，TSLP促进CD4T细胞的发育，而IL-7和IL-15也具有相同的GC，促进CD8T细胞的发育，TSLP在哮喘小鼠过敏性肺部炎症模型的发展中起关键作用，而CD4+T细胞在该模型中的作用是必不可少的。在过去的一年里，我们证明并报道了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在人和小鼠原代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，并提供了第一个使用JAK1和JAK2组合的细胞因子来介导STAT5激活的例子。我们之前还证明了已知对TSLP有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是自分泌机制。利用Arya Biragyn，我们还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，并产生IL-10和IL-13。 在过去的一年里，我们在日本的N.Hirasawa报道，TSLP的反应性对于palifermin介导的移植物抗宿主疾病的保护是必需的，而且，TSLP是由二甲苯诱导的，并与苦味酸诱导的过敏性炎症的加重有关。在多伦多与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。我们在小鼠蜕膜中发现了表达IL-7ra的细胞，并发现其在子宫NK细胞亚群中表达，子宫NK细胞也表达TSLPR。正常妊娠时子宫NK细胞的发育不需要IL-7或TSLP，但每种细胞因子在不同的着床区域对子宫NK细胞都有功能影响。我们还继续对与过敏性炎症有关的TSLP进行研究。 总体而言，这些研究增加了我们对GC家族细胞因子和TSLP信号转导的理解，阐明了与免疫缺陷、过敏、自身免疫和癌症以及淋巴系统动态平衡相关的分子机制。

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.