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: 8939802
• 负责人: Warren J Leonard
• 金额: $ 127.63万
• 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/8939802
• 关键词: Allergic; Autoimmunity; BCL6 gene; Binding; Biology; Boxing; CD27 Antigens; Cell Differentiation process; Cell physiology; Cells; ChIP-seq; Clinical; Collaborations; Complex; Coupled; Cytokine Receptors; DNA Sequence Analysis; Development; Disease; Event; Family; Genes; Goals; Helminths; Host Defense; Human; Hypersensitivity; IL7R gene; Immune; Immune System Diseases; Immune response; Immune system; Immunologic Deficiency Syndromes; Immunology; Inflammatory; Inflammatory Bowel Diseases; Inherited; Interleukin 2 Receptor Gamma; Interleukin-15; Interleukin-17; Interleukin-2; Interleukin-4; Interleukin-7; Interleukin-9; JAK3 gene; Malignant Neoplasms; Mediating; Molecular; Mus; Mutate; Mutation; Nature; Paper; Phenotype; Phosphotransferases; Physiological; Proteins; Psoriasis; Publishing; Regulation; Reporting; Role; STAT5A gene; STAT5B gene; Signal Transduction; System; T-Lymphocyte; T-bet protein; Th2 Cells; Time; Variant; Virus; Work; X-Linked Severe Combined Immunodeficiency; base; chromatin immunoprecipitation; cytokine; genome-wide; human disease; improved; in vivo; inhibitor/antagonist; insight; interleukin-12 receptor; neoplastic; novel; pathogen; promoter; receptor; three dimensional structure

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. T helper cell differentiation is critical for normal immune responses, with Th1 differentiation being important for host defense to viruses and other intracelllular pathogens, Th2 differentiation being vital in allergic disorders and related to helminths, and Th17 differentiation being vital in a range of inflammatory disorders, including psoriasis and inflammatory bowel disease. We previously showed that IL-2 is important for Th2 differentiation and reported that IL-2 regulates expression of the IL-4 receptor in a STAT5-dependent manner and critically controls priming of cells for Th2 differentiation. Moreover, using genome-wide Illumina-based ChIP-Seq (chromatin immunoprecipitation coupled to DNA sequencing) analysis, we had discovered broad regulation of Th2 differentiation via STAT5A and STAT5B. Moreover, we had discovered that IL-2-mediated IL-4Ra induction was critical in priming cells for Th2 differentiation. We then had substantially extended these findings by showing that IL-2 via STAT5 induces expression of IL-12Rb1 and IL-12Rb2 and that the induction of IL-12Rb2 is critical for Th1 differentiation and we defined the mechanism of regulation of IL-12Rb2. Additionally, we previously showed that IL-2 via STAT5 also regulates the T box protein, T-bet, and that in contrast to the induction of IL-12R proteins, IL-2 inhibits expression of IL-6Ra and gp130, helping to explain the inhibition of Th17 differentiation. Consistent with the ability of Tbx21 to inhibit Th17 differentiation, expression of Tbx21 in Th17 cells resulted in increased IFNg but decreased expression of IL-17A. These results indicated a very broad effect of IL-2 via STAT5 on T helper cell differentiation. In the current year, we had a major paper reporting the critical role of IL-2 in Th9 differentiation. We demonstrated a direct effect of IL-2 on Th9 differentiation via its induction of STAT5 binding to the Il9 promoter. Moreover, we showed opposing actions of IL-2 and IL-21 in Th9 differentiation based on their differential regulation of BCL6, which is induced by IL-21 but repressed by IL-2. We also have continued our studies of the role of STAT5 tetramerization in vivo. We previously collaborated with Dr. K. Christopher Garcia at Stanford on a project in which the three dimensional structure of IL-2 complexed to its receptor was compared to that of IL-15 bound to its receptor. These studies had been published in Nature Immunology and provided key mechanistic and structural insights into the functional differences between IL-2 and IL-15. During the current year, we continued our collaboration with Dr. Garcia, studying the actions of wild type IL-2 versus novel IL-2 variants, a project with potential clinical ramifications. Some of the IL-2 variants are potent inhibitors of both IL-2 and IL-15, and some have partial agonistic activity. These may have clinical potential, including in cancer and in immunological diseases. Moreover, the approach used to generate these novel IL-2 variants should be broadly applicable to other gc family cytokines and potentially other type 1 cytokines as well. We also have the long-term goal of identifying new causes of inherited human immunodeficiency. 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, including 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。我们先前还表征了由IL-2，IL-4，IL-7和IL-15诱导或抑制的基因。 T辅助细胞分化对于正常的免疫反应至关重要，Th1的分化对于宿主防御对病毒和其他细胞内病原体至关重要，Th2分化在过敏性疾病中至关重要，并且与舵机有关，TH17分化对于包括牛皮癣和炎症性弓箭疾病在内的炎症性疾病中至关重要。我们先前表明，IL-2对于TH2分化很重要，并报告IL-2以STAT5依赖性方式调节IL-4受体的表达，并严格控制细胞的TH2分化启动。此外，使用基于全基因组光明的CHIP-SEQ（染色质免疫沉淀与DNA测序结合）分析，我们通过Stat5a和Stat5b发现了对TH2分化的广泛调节。此外，我们发现IL-2介导的IL-4RA诱导对于Th2分化的启动细胞至关重要。然后，我们通过证明IL-2通过STAT5诱导IL-12RB1和IL-12RB2的表达来大大扩展了这些发现，并且IL-12RB2的诱导对于Th1的差异至关重要，我们定义了IL-12RB2调节的机制。此外，我们先前表明，IL-2通过STAT5还调节T盒蛋白T-bet，与诱导IL-12R蛋白的诱导相反，IL-2抑制了IL-6RA和GP130的表达，有助于解释Th17差异的抑制。与TBX21抑制Th17分化的能力一致，Th17细胞中TBX21的表达导致IFNG增加，但IL-17A的表达降低。这些结果表明IL-2通过STAT5对T辅助细胞分化的影响非常广。 在当年，我们有一篇主要论文报告了IL-2在TH9差异化中的关键作用。我们通过诱导STAT5与IL9启动子的结合来证明IL-2对TH9分化的直接影响。此外，我们基于其BCl6的差异调节在TH9分化中显示了IL-2和IL-21的相反作用，这是由IL-21诱导的，但受IL-2的抑制作用。我们还继续研究体内STAT5四聚体的作用。 我们之前曾与斯坦福大学的K. Christopher Garcia博士合作，该项目将IL-2的三维结构与其受体的IL-15进行了比较。这些研究已在自然免疫学上发表，并为IL-2和IL-15之间的功能差异提供了关键的机械和结构见解。在当年，我们继续与Garcia博士进行合作，研究了野生IL-2与新型IL-2变体的行为，这是一个潜在的临床影响的项目。一些IL-2变体是IL-2和IL-15的有效抑制剂，有些具有部分激动活性。这些可能具有临床潜力，包括癌症和免疫疾病。此外，用于生成这些新型IL-2变体的方法应广泛适用于其他GC家族细胞因子和潜在的其他1型细胞因子。 我们还具有确定遗传性人类免疫缺陷的新原因的长期目标。 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，包括过敏，自身免疫性和癌症。