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: 9572285
• 负责人: Warren J Leonard
• 金额: $ 127.76万
• 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/9572285
• 关键词: Adult; Antineoplastic Agents; Apoptosis; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; BCL1 Oncogene; Binding; Biological; Biology; CASP1 gene; CASP8 gene; CD27 Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Caspase; Cell Count; Cell Differentiation process; Cell Survival; Cell physiology; Cells; Cessation of life; Child; Chronic; Collaborations; Collagen-Induced Arthritis; Crohn' s disease; Cytokine Receptors; Data; Dendritic Cells; Development; Elements; Endothelial Cells; Event; Family; Gene Expression Regulation; Genes; Granulocyte-Macrophage Colony-Stimulating Factor; Helper-Inducer T-Lymphocyte; Hepatitis A; Hepatitis B; Hindlimb; Human; Hypoxia; IL1B gene; IL7R gene; IRF4 gene; ITGAX gene; Immune; Immune response; Immunoglobulins; Immunological Models; Impairment; Infection; Inflammasome; Inflammatory Response; Innate Immune System; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Interferons; Interleukin 2 Receptor; Interleukin 2 Receptor Gamma; Interleukin-1; Interleukin-1 Receptors; Interleukin-10; Interleukin-15; Interleukin-2; Interleukin-4; Interleukin-7; Interleukin-9; Ischemia; JAK3 gene; Job' s Syndrome; Knockout Mice; Knowledge; Laboratories; Lung; Lupus; Lymphocytic Choriomeningitis; Malignant Neoplasms; Manuscripts; Mediating; Mediator of activation protein; Memory; Murine pneumonia virus; Mus; Mutate; Mutation; Natural Immunity; Neutrophil Infiltration; PRDM1 gene; Pathogenicity; Pathologic; Pathologic Processes; Pathway interactions; Patients; Perfusion; Peripheral Vascular Diseases; Peripheral arterial disease; Phase; Phenotype; Phosphotransferases; Physiological; Play; Process; Production; Proto-Oncogene Proteins c-jun; Psoriasis; Receptor Activation; Receptor Signaling; Recovery; Regulation; Reporting; Respiratory syncytial virus; Response Elements; Role; STAT1 gene; STAT3 gene; Serine Protease; Signal Transduction; System; T-Lymphocyte; Time; Transcription Factor AP-1; Transgenic Mice; Up-Regulation; Vaccinia; Viral; Virus Diseases; Work; Writing; X-Linked Severe Combined Immunodeficiency; age related; antitumor agent; autoimmune uveitis; base; cell type; cytokine; gain of function; gene induction; human disease; immune system function; interest; interleukin-21 receptor; mouse model; neonate; neoplastic; novel; prevent; receptor; response; transcription factor; transcriptome sequencing; γδ T cells

IL-2 and related cytokine 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 co-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 with Dan Littman (NYU) that IL-21 can promote the differentiation of Th17 cells (which mediate pathological processes such as Crohn's disease and psoriasis), and critically regulates immunoglobulin production. We and others implicated IL-21 as serving a key role in autoimmune disease, including lupus and type 1 diabetes, and indicated the possible utility of IL-21 as an anti-tumor agent. 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. We also previously found that IL-21 signaling is required for CD8 T cell survival and memory cell formation in response to vaccinia viral infection and contributed to a study showing that IL-21 was pivotal in determining age-dependent immune responses in a mouse model of hepatitis, a finding that helps to explain 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. We previously also found that IL-21 promotes the pathogenic response to pneumonia virus of mice (PVM), which is highly related to human respiratory syncytial virus. Interestingly, after infection of Il21r-deficient mice with PVM, there was less infiltration of neutrophils and fewer CD8, CD4, and gamma-delta T cell numbers in the lungs. These data indicated that IL-21 plays an important role in mediating the inflammatory response to PVM and suggest that inhibiting the action of IL-21 could represent a mechanism for treatment PVM and potentially other viral infections. Finally, with Tom Tedder, we previously showed that IL-21 could expand B regulatory cells that produce IL-10 (B10 cells). In the current year, we have continued a broad range of extensive studies related to the biological actions of IL-21, including on additional cell types. Previously, we demonstrated that IL-21 regulated expression of the Prdm1 gene that encodes BLIMP1 via a response element that depends on STAT3 and IRF4. This led to our prior discovery that in contrast to its ability to cooperate with PU.1 in B cells to act via Ets-IRF composite elements (EICEs), IRF4 cooperates with BATF/JUN family proteins to act via AP1-IRF composite elements (AICEs) in T cells, as well as in B cells. We demonstrated critical regulation of important genes via these AICEs and demonstrated cooperative binding of IRF4, BATF, and JUN family proteins, with markedly diminished IRF4 binding in Batf-deficient cells and markedly diminished BATF binding in Irf4-deficient cells. In the current year, we have extended studies, including contributing to studies related to IRF8 in collaboration with the lab of H.C. Morse. IL-21 has broad actions on T- and B-cells, but its actions in innate immunity are poorly understood. Previously, we reported that IL-21 induces apoptosis of conventional dendritic cells (cDCs) via STAT3 and Bim, and this was inhibited by granulocyte-macrophage colony-stimulating factor (GM-CSF). Importantly, the canonical pathway for IL-1 production requires TLR-mediated NF-B-dependent Il1b gene induction, followed by caspase-containing inflammasome-mediated processing of pro-IL-1. We also previously showed that IL-21 unexpectedly induces IL-1 production in conventional dendritic cells (cDCs) via a STAT3-dependent but NF-B-independent pathway. IL-21-induced IL-1 processing in cDCs does not require caspase-1 or caspase-8 but depends on IL-21-mediated death and activation of serine protease(s). Moreover, STAT3-dependent IL-1 expression in cDCs at least partially explains the IL-21-mediated pathologic response occurring during infection with pneumonia virus of mice. We also previously showed that IL-1 receptor signaling is critical for the development of autoimmune uveitis, a process we previously showed was dependent on IL-21. Mechanistically, although IL-21 can activate several STAT family transcription factors, our previous studies revealed that in addition to its mainly signaling via STAT3, STAT1 is also important, with RNA-Seq analysis of CD4(+) T cells from Stat1- and Stat3-deficient mice revealing that both STAT1 and STAT3 are critical for IL-21-mediated gene regulation. We previously showed that expression of Tbx21 and Ifng was differentially regulated by these two STATs, with opposing actions of STAT1 and STAT3 on IFN- expression in CD4(+) T cells during chronic lymphocytic choriomeningitis infection, and moreover, concordant actions of IL-21 related to IFNG and TBX21 expression was found using CD4(+) T cells from patients with autosomal dominant hyper-IgE syndrome, which is caused by STAT3 deficiency, as well as in cells from STAT1 gain-of-function patients, so that STAT1 vs. STAT3 activation is a mechanism of fine tuning the actions of IL-21. We also previously demonstrated opposing roles for IL-21 and IL-2 in T helper 9 cell differentiation and that this was based in part on the induction of BCL-6 by IL-21, and we contributed to studies showing that IL-21 interacts with IFNg and IL-4 to govern TBET and CD11c expression in TLR-activated B cells, and that IL-21 signaling in B cells but not T cells is essential for the development of collagen-induced arthritis in mice. In ongoing work, we have studied the roles of IL-21 in other immunological models, including related to the innate immune system, and generated a large amount of new data on signaling by IL-21 and elucidating novel actions of this cytokine, including on new cell types, and we have begun to write manuscripts related to these studies. Moreover, in collaboration with Dr. Brian Annex, we previously reported that the loss of interleukin-21 receptor activation in hypoxic endothelial cells impairs perfusion recovery after hindlimb ischemia and that there is up-regulation of endothelial IL-21 receptor in peripheral artery disease. We are continuing this valuable collaboration. Overall, these studies have elucidated the biology and mechanisms of action by the gc family cytokine IL-21.They have expanded our knowledge of normal and pathological immune cell function and are relevant to autoimmunity and cancer, as well as to the basic control of T-cell and B-cell actions, and to peripheral vascular disease.

正在研究IL-2和相关的细胞因子系统，以阐明正常，肿瘤和免疫缺陷型状态下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，我们于1986年共同发现IL-2RB，并于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，具有T t-B+NK-NK-表型）。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。 与IL-21相关的，我们先前克隆了IL-21受体，生成IL-21转基因小鼠和IL-21R敲除小鼠，阐明了IL-21信号传导的机制，与丹·利特曼（NYU）（NYU）一起表明，IL-21可以促进Th17细胞的分化（诸如Croliase and Croliase and Crohs''的病理和crolys sissiul and Croly's病态，免疫球蛋白产生。我们和其他人牵涉IL-21在包括狼疮和1型糖尿病在内的自身免疫性疾病中起关键作用，并指出IL-21作为抗肿瘤剂的可能效用。我们还分析了与T卵泡辅助细胞和Th17细胞发展有关的IL-21的作用，并在一项协作研究中生成了数据，即IL-21在后期同酶同种异体反应中是抗抗胆碱性细胞因子。我们先前还发现，IL-21信号是CD8 T细胞存活和记忆细胞对病毒感染的响应而需要的，并有助于一项研究，表明IL-21在确定肝炎的小鼠模型中确定年龄依赖性的免疫反应至关重要新生儿和儿童的HBV。我们以前还发现，IL-21促进了对小鼠（PVM）的肺炎病毒的致病反应，该病毒与人类呼吸道综合病毒高度相关。有趣的是，在感染了IL21R缺陷的小鼠PVM之后，肺中性粒细胞的浸润较小，CD8，CD4和Gamma-delta T细胞中的浸润较少。这些数据表明，IL-21在介导对PVM的炎症反应中起重要作用，并表明抑制IL-21的作用可以代表治疗PVM的机制以及潜在的其他病毒感染。最后，在汤姆·特德（Tom Tedder）的情况下，我们先前表明IL-21可以扩大产生IL-10（B10细胞）的B调节细胞。在当年，我们持续了与IL-21的生物学作用有关的广泛研究，包括其他细胞类型。 以前，我们证明IL-21通过依赖于STAT3和IRF4的响应元件编码BLIMP1的PRDM1基因的表达。这导致我们先前发现的是，与它与B细胞中PU.1合作通过ETS-IRF复合元件（EICES）起作用的能力相反，IRF4与BATF/JUN家族蛋白合作通过T细胞中的AP1-IRF复合元件（AICS）与BATF/JUN家族蛋白合作。我们通过这些AICS证明了对重要基因的关键调节，并证明了IRF4，BATF和JUN家族蛋白的合作结合，在BATF缺陷细胞中的IRF4结合显着降低，并且在IRF4缺乏细胞中的BATF结合显着降低。在当年，我们进行了扩展研究，包括与H.C的实验室合作为与IRF8有关的研究做出了贡献。莫尔斯。 IL-21对T型和B细胞有广泛的行动，但其先天免疫的行为知之甚少。以前，我们报道了IL-21通过STAT3和BIM诱导常规树突状细胞（CDC）凋亡，这受到粒细胞 - 巨噬细胞刺激因子（GM-CSF）的抑制。重要的是，IL-1产生的规范途径需要TLR介导的NF-B依赖性IL1B基因诱导，然后进行含CASPase的炎性炎症体介导的Pro-IL-1处理。我们先前还表明，IL-21意外地通过STAT3依赖性但NF-B独立的途径在常规的树突状细胞（CDC）中诱导IL-1产生。 IL-21诱导的CDC中IL-1处理不需要CASPASE-1或CASPASE-8，而取决于IL-21介导的丝氨酸蛋白酶的死亡和激活。此外，CDC中的STAT3依赖性IL-1表达至少部分解释了小鼠肺炎病毒感染期间IL-21介导的病理反应。我们先前还表明，IL-1受体信号对于自身免疫性葡萄膜炎的发展至关重要，我们先前显示的过程取决于IL-21。 从机械上讲，尽管IL-21可以激活几个Stat家族转录因子，但我们先前的研究表明，除了主要通过STAT3信号传导外，STAT1也很重要，并且对来自STAT1和Stat3缺陷型小鼠的CD4（+）T细胞的RNA-SEQ分析也表明，STAT1和Stat3均表明IL-21介导的基因介导的基因介导的基因均至关重要。我们先前表明，TBX21和IFNG的表达受这两个统计数据的差异调节，在慢性淋巴细胞性粘性炎感染过程中，STAT1和Stat3对CD4（+）T细胞IFN-表达的作用相反，此外，与IFNG和TBX21的IL-21患者相关的IL-21的一致作用与CD4相关的一致性相关，发现了与CD4相关的CD4（+）TRINDERS TRINGERS，+ILLEDIER与CD4（+）TRINDER相关。这是由STAT3缺乏症以及STAT1功能获得患者的细胞引起的，因此STAT1与STAT3激活是一种微调IL-21作用的机制。我们先前还证明了T辅助9细胞分化中IL-21和IL-2的相对作用，这部分基于IL-21的BCl-6诱导，我们为研究表明IL-21与IFNG和IL-4相互作用的研究促进了IFNG和IL-4的相互作用，以控制TBET和CD11C在TLR激活的B细胞和CD11C中的IS ISS ISS ISS IL-IL-21，但在IL-21中的开发中，它是IL-21的信号。小鼠胶原蛋白引起的关节炎。在正在进行的工作中，我们研究了IL-21在其他免疫学模型中的作用，包括与先天免疫系统有关，并通过IL-21产生了大量有关信号的新数据，并阐明了这种细胞因子的新作用，包括新细胞类型，我们已经开始写与这些研究相关的手稿。 此外，与Brian Annex博士合作，我们先前报道说，缺氧内皮细胞中白介素-21受体激活的丧失会损害后肢缺血后的灌注恢复，并且外周动脉疾病中内皮IL-21受体的上调上调。我们正在继续这种有价值的合作。 总体而言，这些研究阐明了GC家族细胞因子IL-21的生物学和作用机制。它们扩大了我们对正常和病理免疫细胞功能的了解，并且与自身免疫和癌症以及T细胞和B细胞作用的基本控制以及与外周血管疾病有关。