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

基本信息

批准号：
8557959
负责人：
Warren J Leonard
金额：
$ 134.67万
依托单位：
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
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/8557959
关键词：
Adoptive Transfer Adult Animals Antibody Formation Antineoplastic Agents Attenuated Autoimmune Diabetes Autoimmune Diseases Autoimmunity B-Lymphocytes Binding Biology CD27 Antigens CD4 Positive T Lymphocytes CD8B1 gene Cell Count Cell Survival Cells Child Chimeric Proteins Chronic Collaborations Crohn&apos s disease Cytokine Receptors Data Dendritic Cells Development Diabetes Mellitus Disease Elements Event Exhibits Experimental Autoimmune Encephalomyelitis Family Genes Helper-Inducer T-Lymphocyte Hepatitis Hepatitis B Virus Human Human respiratory syncytial virus IL7R gene IRF4 gene Immune response Immune system Immunoglobulins Indium Infection Inflammatory Response Interleukin 2 Receptor Gamma Interleukin-10 Interleukin-15 Interleukin-17 Interleukin-2 Interleukin-4 Interleukin-7 Interleukin-9 JAK3 gene Knockout Mice Leucine Zippers Lung Lupus Malignant Neoplasms Mediating Mediator of activation protein Memory Murine pneumonia virus Mus Mutate Mutation Neutrophil Infiltration PRDM1 gene Pathologic Processes Patients Phase Phase II Clinical Trials Phenotype Phosphotransferases Physiological Play Pneumovirus Production Proto-Oncogene Proteins c-jun Regulation Reporting Response Elements Retina Role STAT3 gene Signal Transduction Symptoms System Systemic Lupus Erythematosus T-Lymphocyte TNFRSF5 gene Time Transcription Factor AP-1 Transgenic Mice Transplantation Vaccinia Vaccinium Viral Virus Virus Diseases Wild Type Mouse Work X-Linked Severe Combined Immunodeficiency age related antitumor agent autoimmune uveitis base cytokine graft vs host disease human disease interleukin-21 receptor leukemia mouse model neonate neoplastic novel therapeutics prevent receptor response

项目摘要

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. We also previously showed that IL-21 is critical for graft versus host disease (GVHD) in a mouse model, and thus 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. 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 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. We also had 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 reportermice, and found IL-2/IL-21 double producing cells in the retina. In the past year, we reported that IL-21 can promote the pathogenic response to a virus. In particular, we studied pneumonia virus of mice (PVM), or pneumovirus, which is highly related to human respiratory syncytial virus. PVM-infected mice expressed IL-21 in CD4+ T cells. Interestingly, after infection Il21r-deficient mice had less infiltration of neutrophils, as well as fewer CD8, CD4, and gamma-delta T cell numbers in the lungs. Strikingly, Il21r-deficient mice exhibited enhanced survival, and treatment of wild type mice with an IL-2R-Fc fusion protein enhanced the survival of these animals. These data indicate that IL-21 plays an important role in mediating the inflammatory response to PVM and suggest that inhibiting the action of PVM could represent a mechanism for treatment PVM and potentially other viral infections. In other collaborative studies, we built on earlier studies demonstrating a key role for IL-21 in diabetes and reported that IL-21 has anti-tolerogenic activity related to the late-phase alloimmune response. In another collaborative study, we also reported that IL-17 derived from Th17 cells is not required for antibody production from B lymphocytes. 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 discovering in the past year that in contrast to its known 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 cooperative 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. We demonstrated critical regulation of key genes, including for example those encoding IL-10 and IL-17 via AICEs. In collaborative studies with Ken Murphy, we also demonstrated important compensatory roles for BATF factors in dendritic cell development mediated by BATF-IRF interactions involving the leucine zipper domain of BATF. In another collaborative study with Tom Tedder, we investigated the role of IL-21 in the expansion regulatory B cells, which produce IL-10 (B10 cells). Corresponding to our earlier findings that IL-21 potently induces expression of IL-10, we demonstrated that regulatory B cells control T cell autoimmune disease via IL-21 and CD40 dependent cognate interactions and that ex vivo signaling via IL-21 and CD40 allowed dramatic expansion of effector B10 cells that could markedly decrease disease symptoms in animals with established experimental autoimmune encephalitis. Overall, our studies have elucidated the biology and mechanism of action by the gc family cytokine IL-21. Our findings are relevant to autoimmunity and cancer, as well as to the basic control of T-cell and B-cell actions.

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。与IL-21相关的是，我们先前克隆了IL-21受体，产生了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，表明IL-21驱动了Th17细胞的分化（在Crohny Pistion等病理过程中很重要），并受到质疑的危害，这些过程在病理学过程中受到了危害。一系列数据还暗示IL-21在自身免疫性中起可能作用，尤其是在狼疮中，狼疮的BXSB-YAA小鼠模型中的IL-21水平升高。此外，实验室的先前研究表明，IL-21可能是抗肿瘤剂的实用性。我们先前表明，IL-21在自身免疫性糖尿病中起着至关重要的作用，在2009年期间，在杰克逊实验室与Derry Roopenian合作时，我们证明了IL-21信号传导对于在BXSB-yaa小鼠SLE的BXSB-YAA Mode Model of SLE的系统性狼疮的发展至关重要。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。我们先前还表明，IL-21对于小鼠模型中的移植物与宿主疾病（GVHD）至关重要，因此阻断IL-21可能代表了一种新颖的治疗策略，用于减弱或防止与移植相关的问题。此外，我们证明IL-21通过增强效应CD4 T细胞的产生来促进GVHD。有趣的是，我们还表明，基于IL-21信号传导，GVL和移植物与宿主疾病（GVHD）是可观的可区分事件。此外，在没有CD8 T细胞的情况下，缺乏IL-21信号会减弱移植物与白血病（GVL）。我们先前还发现，CD8 T细胞存活和记忆细胞对病毒感染的响应是必需的IL-21信号传导，并且IL-21在确定肝炎模型中确定年龄依赖性免疫反应的关键性是关键的，这一发现在可能降低了年轻患者的批判性CD8的可能性下，这一发现具有广泛的意义，该发现可能会降低IL-21的生产，并降低IL-21的生产。在新生儿和儿童中。我们还证明，在类似的人类疾病的小鼠模型中，IL-21对于开发实验性自身免疫性葡萄膜炎至关重要，并且显示出IL-21R缺陷型T细胞对疾病疾病显着有缺陷。实际上，我们产生了IL-2-Emerald GFP/IL-21-MCHERRY双重记录，并在视网膜中发现了IL-2/IL-21双重产生细胞。在过去的一年中，我们报告说IL-21可以促进对病毒的致病反应。特别是，我们研究了小鼠（PVM）或肺炎病毒的肺炎病毒，该病毒与人类呼吸道合胞病毒高度相关。 PVM感染的小鼠在CD4+ T细胞中表达IL-21。有趣的是，在感染后，IL21R缺陷型小鼠的嗜中性粒细胞浸润较少，肺中的CD8，CD4和Gamma-delta T细胞数较少。引人注目的是，IL21R缺陷型小鼠的生存率增强，用IL-2R-FC融合蛋白对野生型小鼠进行治疗增强了这些动物的存活。这些数据表明，IL-21在介导对PVM的炎症反应中起着重要作用，并表明抑制PVM的作用可以代表治疗PVM的机制以及潜在的其他病毒感染。在其他协作研究中，我们基于早期的研究，证明IL-21在糖尿病中的关键作用，并报告IL-21具有与后期同类同种免疫反应相关的抗胆固性活性。在另一项协作研究中，我们还报道说，从B淋巴细胞产生抗体的IL-17不需要Th17细胞。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。这导致我们在过去的一年中发现，与已知与B细胞中PU.1合作通过ETS-IRF复合元件（EICES）作用的能力相比，IRF4与BATF/JUN家族蛋白合作通过T细胞中的AP1-IRF复合元素（AICE）和B细胞以及B细胞以及在B细胞中合作。我们证明了通过这些AICS对重要基因进行关键的合作调节，并证明了IRF4，BATF和JUN家族蛋白的合作结合，并且在BATF缺陷型细胞中的IRF4结合显着降低，并且在IRF4缺乏细胞中显着减少了BATF的结合。我们证明了关键基因的批判性调节，包括例如那些通过AICE编码IL-10和IL-17的人。在与肯·墨菲（Ken Murphy）的合作研究中，我们还证明了BATF因子在涉及BATF的Leucine Zipper域介导的树突状细胞发育中的BATF因子的重要补偿作用。在与Tom Tedder的另一项合作研究中，我们研究了IL-21在产生IL-10（B10细胞）的扩展调节B细胞中的作用。与我们较早的发现相对应的IL-21有效诱导IL-10的表达，我们证明了调节性B细胞通过IL-21和CD40依赖的Cognate相互作用来控制T细胞自身免疫性疾病，并且通过IL-21和CD40进行了体内信号传导，可以在效应B10细胞中显着降低了疾病的疾病症状，从而使效应B10细胞的扩张巨大降低了实验。总体而言，我们的研究阐明了GC家族细胞因子IL-21的生物学和作用机理。我们的发现与自身免疫性和癌症以及T细胞和B细胞作用的基本控制有关。