IL-2 Family Cytokines and their Receptors-- Biology of the IL-21 system

IL-2 家族细胞因子及其受体——IL-21 系统的生物学

• 批准号: 8344812
• 负责人: Warren J Leonard
• 金额: $ 125.24万
• 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/8344812
• 关键词: Adoptive Transfer; Adult; Appearance; Attenuated; Autoimmune Diabetes; Autoimmunity; B-Cell Development; B-Lymphocytes; Biology; CD27 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Maturation; Cell Survival; Cells; Cellular biology; Child; Chronic; Collaborations; Crohn' s disease; Cytokine Receptors; Data; Development; Disease; Event; Family; Genes; Helper-Inducer T-Lymphocyte; Hepatitis; Hepatitis B Virus; Human; IL7R gene; Immune response; Immune system; Immunoglobulins; Interleukin 2 Receptor Gamma; Interleukin-15; Interleukin-2; Interleukin-4; Interleukin-7; Interleukin-9; JAK3 gene; Knockout Mice; Lupus; Malignant Neoplasms; Memory; Molecular; Mus; Mutate; Mutation; Pathologic Processes; Patients; Phase; Phenotype; Phosphotransferases; Physiological; Play; Production; Reporter; Reporting; Retina; Role; Signal Transduction; System; Systemic Lupus Erythematosus; T-Lymphocyte; Time; Transgenic Mice; Transplantation; Vaccinia; Vaccinium; Viral; Virus Diseases; Work; X-Linked Severe Combined Immunodeficiency; age related; antitumor agent; autoimmune uveitis; base; cytokine; graft vs host disease; human disease; improved; interleukin-21 receptor; leukemia; mouse model; neonate; neoplastic; novel therapeutics; prevent; progenitor; receptor; response

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. Related to IL-21, we previously cloned the IL-21 receptor, generated IL-21 transgenic mice and IL-21R knockout mice, elucidated the mechanism of IL-21 signaling, showed that IL-21 drives the differentiation of Th17 cells (which are important in pathological processes such as Crohn's disease), and critically regulates immunoglobulin production. A range of data also implicated IL-21 as serving a possible role in autoimmunity, particularly in lupus, with elevated IL-21 levels in the BXSB-Yaa mouse model of lupus. Moreover, prior studies from the lab indicated the possible utility of IL-21 as an anti-tumor agent. We previously showed that IL-21 plays a critical role in autoimmune diabetes, and during 2009, in a collaboration with Derry Roopenian at the Jackson Lab, we demonstrated that IL-21 signaling is essential for the development of systemic lupus erythematosus in the BXSB-Yaa mouse model of SLE. We also analyzed the role of IL-21 related to the development of T follicular helper cells and Th17 cells and generated data in a collaborative study that IL-21 is anti-tolerogenic cytokine in the late-phase alloimmune response. In collaborative studies, we showed that IL-21 is critical for graft versus host disease (GVHD) in a mouse model. These data suggest that IL-21 is an important regulator of GVHD and that blocking IL-21 could represent a novel therapeutic strategy for attenuating or preventing this problem associated with transplantation. Moreover, we demonstrated that IL-21 promotes GVHD through enhanced production of effector CD4 T cells. Interestingly, we also showed that GVL and graft versus host disease (GVHD) are immunologically distinguishable events based on IL-21 signaling. Moreover, the lack of an IL-21 signal attenuates graft versus leukemia (GVL) in the absence of CD8 T cells. Extending earlier studies on the role of IL-21 in B cell biology, IL-21R was shown to be functional as early as pro-B cells and the addition of IL-21 to B cell progenitors resulted in the appearance of B cell maturation markers. The data collectively supported an early role for IL-21 in regulating B cell development. It was also revealed that IL-21 signaling is required for CD8 T cell survival and memory cell formation in response to vaccinia viral infection and that IL-21 was pivotal in determining age-dependent immune responses in a mouse model of hepatitis, a finding with broad implications in potentially explaining why decreased production of IL-21 in younger patients may prevent critical CD8 T and B cell responses, with viral clearance in most adults and chronic HBV in neonates and children. Finally, we demonstrated that IL-21 is critical for the development of experimental autoimmune uveitis in a mouse model of a similar human disease and showed markedly defective adoptive transfer of disease by IL-21R-deficient T cells. We in fact generated IL-2-emerald GFP/IL-21-mCherry dual reporter mice, and found IL-2/IL-21 double producing cells in the retina. Overall, our studies help to improve our understanding of signaling by the gc family cytokine IL-21. Our findings clarify molecular mechanisms that are relevant to autoimmunity, and cancer, as well as to the basic control of T-cell and B-cell actions.

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。 与IL-21相关，我们先前克隆了IL-21受体，产生了IL-21转基因小鼠和IL-21 R敲除小鼠，阐明了IL-21信号传导的机制，表明IL-21驱动Th 17细胞的分化（这在克罗恩病等病理过程中很重要），并严格调节免疫球蛋白的产生。一系列数据还暗示IL-21在自身免疫中起可能的作用，特别是在狼疮中，在狼疮的BXSB-Yaa小鼠模型中IL-21水平升高。此外，来自实验室的先前研究表明IL-21作为抗肿瘤剂的可能效用。我们之前已经证明IL-21在自身免疫性糖尿病中起着关键作用，2009年，我们与杰克逊实验室的德里罗彭尼安合作，在BXSB-Yaa SLE小鼠模型中证明了IL-21信号传导对系统性红斑狼疮的发展至关重要。我们还分析了IL-21与T滤泡辅助细胞和Th 17细胞发育相关的作用，并在一项合作研究中获得了IL-21是晚期同种免疫应答中的抗耐受性细胞因子的数据。 在合作研究中，我们发现IL-21在小鼠模型中对移植物抗宿主病（GVHD）至关重要。这些数据表明，IL-21是GVHD的重要调节因子，阻断IL-21可能代表一种新的治疗策略，用于减轻或预防与移植相关的这一问题。此外，我们证明了IL-21通过增强效应CD 4 T细胞的产生来促进GVHD。有趣的是，我们还发现GVL和移植物抗宿主病（GVHD）是基于IL-21信号传导的免疫学上可区分的事件。此外，在不存在CD 8 T细胞的情况下，IL-21信号的缺乏减弱了移植物抗白血病（GVL）。 扩展了IL-21在B细胞生物学中作用的早期研究，显示IL-21 R早在前B细胞中起作用，并且将IL-21添加到B细胞祖细胞中导致B细胞成熟标志物的出现。这些数据共同支持IL-21在调节B细胞发育中的早期作用。 还揭示了IL-21信号传导是响应于牛痘病毒感染的CD 8 T细胞存活和记忆细胞形成所需的，并且IL-21在确定肝炎小鼠模型中的年龄依赖性免疫应答中是关键的，这一发现在潜在地解释为什么年轻患者中IL-21产生的减少可能阻止关键的CD 8 T和B细胞应答方面具有广泛的意义，在大多数成人中病毒清除，在新生儿和儿童中慢性HBV。 最后，我们证明，IL-21是关键的实验性自身免疫性葡萄膜炎的发展在小鼠模型中的一个类似的人类疾病，并显示出明显缺陷的过继转移疾病的IL-21 R-缺陷的T细胞。事实上，我们产生了IL-2-绿宝石GFP/IL-21-mCherry双报告小鼠，并在视网膜中发现了IL-2/IL-21双产生细胞。 总的来说，我们的研究有助于提高我们对gc家族细胞因子IL-21信号传导的理解。我们的发现阐明了与自身免疫和癌症相关的分子机制，以及T细胞和B细胞作用的基本控制。