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

IL-2 家族细胞因子及其受体——IL-2 系统的生物学

• 批准号: 7969127
• 负责人: Warren J Leonard
• 金额: $ 88.01万
• 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/7969127
• 关键词: Adoptive Immunotherapy; Adoptive Transfer; Allergic; Autoimmunity; Biology; CD27 Antigens; CD8B1 gene; Cell Death; Cell Differentiation process; Cell Line; Cell physiology; Cells; Cytokine Receptors; Cytoplasmic Tail; Development; Disease; Effector Cell; Event; Family; Gene Expression Profile; Gene Targeting; Genes; Helminths; Homeostasis; Host Defense; Human; Hypersensitivity; IL7R gene; Immune; Immune response; Immune system; Inflammatory; Inflammatory Bowel Diseases; Interleukin 2 Receptor; Interleukin 2 Receptor Gamma; Interleukin 4 Receptor; Interleukin 7 Receptor; Interleukin-15; Interleukin-2; Interleukin-4; Interleukin-7; Interleukin-9; Knock-in Mouse; Malignant Neoplasms; Mediating; Memory; Molecular; Mus; Mutate; Mutation; Natural Killer Cells; Phenotype; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological; Population; Process; Psoriasis; Regulation; Reporting; Role; Signal Transduction; Specificity; Staging; System; T-Cell Receptor; T-Lymphocyte; Th2 Cells; Thymocyte Development; Time; Transgenic Model; Transgenic Organisms; Virus; Work; X-Linked Severe Combined Immunodeficiency; base; cytokine; extracellular; human disease; improved; interleukin-15 receptor; killings; neoplastic; overexpression; pathogen; programs; receptor; research study

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. We also previously characterized genes that were induced or repressed by IL-2, IL-4, IL-7, and IL-15, including showing the negative regulation of the IL-7 receptor alpha chain, a finding with implications in understanding how IL-2 can promote cell death, and the positive regulation of a dual specificity phosphatase, DUSP5, that negatively regulates IL-2-mediated activation of ERK kinases. T helper cell differentiation is an extremely important process in the regulation of host defense. Th1 differentiation is important for host defense to viruses and other intracelllular pathogens, Th2 differentiation is vital in allergic disorders and related to helminths, and Th17 differentiation is vital in a range of inflammatory disorders, including psoriasis and inflammatory bowel disease. In the past year, we reported that IL-2 importantly regulates expression of the IL-4 receptor and critically controls priming of cells for Th2 differentiation. Using the pmel-1 T cell receptor transgenic model of adoptive immunotherapy, we also pursued studies related to the efficacy of adoptively transferred effector cells in terms of their ability to kill turmors and found that effector T cell populations derived from naive rather than central memory CD8+ T cells mediate superior antitumor activity. These populations had distinct gene expression signatures and developmental programs, with much higher IL-2-induces expression of Eomesodermin in the central memory than naive population cells. Having previously shown that a dual specificity phosphatase, denoted DUSP5, that is induced by IL-2 and thus an IL-2 target gene and demonstrated that transgenic overexpression of DUSP5 results in a block in thymocyte development at the CD4/CD8 double positive stage, indicating a role for ERK kinases in this process and that DUSP5 contributes to immunological tolerance, we have continued work on this important phosphatase. The closest cytokine system to IL-2 is that of IL-15 in that both cytokines share IL-2Rb and the gc but have distinctive alpha chains. IL-15 is particularly important for NK-cell development and function and CD8+ T cell homeostasis. As compared to IL-2Ra, IL-15Ra has a larger cytoplasmic domain. We studied the importance of the IL-15 receptor cytoplasmic domain. IL-15 signals at least in part through a process known as transpresentation whereas so far this mechanism of signaling has not been shown for IL-2. To investigate the role of the IL-15Ra cytoplasmic domain, we generated a chimeric receptor molecule with the extracellular and transmembrane portions of IL-2Ra but the cytoplasmic domain of IL-15Ra and knock-in mice were generated. We performed a range of studies in cells lines and in these mice. Adoptive transfer experiments with the chimeric receptor revealed that the IL-15Ra introcytoplasmic domain is required for normal IL-15Ra function but not for transpresentation. Overall, these studies help to improve our understanding of signaling by gc family cytokines. These findings clarify basic molecular mechanisms that are relevant to normal and pathological immune cell function such as allergy, autoimmunity, and cancer.

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，肿瘤和免疫缺陷态的T细胞免疫反应。通过抗原激活T细胞后，T细胞免疫反应的大小和持续时间由产生的IL-2量，表达的受体水平以及每个事件的时间过程确定。 IL-2受体包含三个链IL-2RA，IL-2RB和GC。伦纳德（Leonard）博士于1984年克隆了IL-2RA，我们在1986年发现了IL-2RB，并在1993年报道说，GC链的突变导致X链的严重合并免疫缺陷（XSCID（XSCID），在人类中具有t-b+nk-nk-nk-emotype）。我们在1995年报道说，与GC相关激酶JAK3的突变导致SCID的常染色体隐性形式与XSCID无法区分，并在1998年无法区分t-b+ NK+ SCID是由IL7R基因中的突变引起的。根据我们实验室和其他实验室的工作，GC先前被IL-2，IL-4，IL-7，IL-9，IL-9，IL-15和IL-21的受体共享。 We also previously characterized genes that were induced or repressed by IL-2, IL-4, IL-7, and IL-15, including showing the negative regulation of the IL-7 receptor alpha chain, a finding with implications in understanding how IL-2 can promote cell death, and the positive regulation of a dual specificity phosphatase, DUSP5, that negatively regulates IL-2-mediated activation of ERK kinases. T辅助细胞分化是调节宿主防御的极其重要的过程。 TH1的分化对于宿主对病毒和其他细胞内病原体非常重要，Th2分化在过敏性疾病中至关重要，并且与蠕虫有关，Th17分化对于包括牛皮癣和炎症性肠病在内的炎性疾病中至关重要。在过去的一年中，我们报道IL-2重要地调节IL-4受体的表达，并严格控制细胞的Th2分化。 我们还使用PMEL-1 T细胞受体转基因模型的收养免疫疗法模型，我们还进行了与收养转移的效应细胞杀死鸡伤的能力相关的研究，并发现效应T细胞群体源自幼稚而不是中央记忆CD8+ T细胞介导了较高的抗肿瘤活性。这些人群具有独特的基因表达特征和发育程序，与幼虫细胞相比，IL-2-诱导艾美胚层的表达更高。 Having previously shown that a dual specificity phosphatase, denoted DUSP5, that is induced by IL-2 and thus an IL-2 target gene and demonstrated that transgenic overexpression of DUSP5 results in a block in thymocyte development at the CD4/CD8 double positive stage, indicating a role for ERK kinases in this process and that DUSP5 contributes to immunological tolerance, we have continued work on this important phosphatase. 最接近IL-2的细胞因子系统是IL-15的细胞因子系统，因为两种细胞因子共享IL-2RB和GC，但具有独特的α链。 IL-15对于NK细胞发育和功能以及CD8+ T细胞稳态尤其重要。与IL-2RA相比，IL-15RA具有较大的细胞质结构域。我们研究了IL-15受体细胞质结构域的重要性。 IL-15信号至少部分通过称为先代的过程，而到目前为止，该信号传导尚未显示为IL-2。为了研究IL-15RA细胞质结构域的作用，我们与IL-2RA的细胞外和跨膜部分产生了一个嵌合受体分子，但产生了IL-15RA的细胞质结构域，并产生了敲门型小鼠。我们在细胞系和这些小鼠中进行了一系列研究。使用嵌合受体的收养转移实验表明，正常的IL-15RA功能需要IL-15RA胞质胞质结构域，但对于跨代理而不是。 总体而言，这些研究有助于提高我们对GC家族细胞因子的信号传导的理解。这些发现阐明了与正常和病理免疫细胞功能有关的基本分子机制，例如过敏，自身免疫性和癌症。