Dendritic cell KLF2/Notch Axis and Th2 Responses to Eukaryotic Pathogens

树突状细胞 KLF2/Notch 轴和 Th2 对真核病原体的反应

• 批准号: 9293248
• 负责人: GEORGE S. DEEPE
• 金额: $ 49.6万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-10 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9293248
• 关键词: Americas; Bacterial Infections; Biological; Breathing; CD4 Positive T Lymphocytes; Cell Death; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chemotactic Factors; Communication; Complement; Data; Defect; Dendritic Cells; Development; Disease; Elements; Embryonic Development; Equilibrium; Eukaryota; Evolution; Family; Genes; Genetic Transcription; Genomics; Health; Helminths; Histoplasma capsulatum; Host resistance; Human; Hypoxia; ITGAX gene; Immune response; Immunity; Impairment; Infection; Innate Immune System; Interleukin-13; Interleukin-4; Investigation; Knowledge; Kruppel-like transcription factors; Lead; Leishmania; Licensing; Ligands; Lung; Mediator of activation protein; Microbe; Molecular Target; Morbidity - disease rate; Morphogenesis; Mus; Myeloid Cells; Natural Immunity; Nitric Oxide; Pathogenicity; Pathway interactions; Phenotype; Population; Process; Production; Property; Recruitment Activity; Regulation; Resistance to infection; Resolution; Role; Severities; Shapes; Signal Transduction; T-Cell Activation; T-Lymphocyte; Testing; Th1 Cells; Up-Regulation; Vacuum; Work; adaptive immunity; antimicrobial; chromatin immunoprecipitation; cytokine; equilibration disorder; extracellular; fungus; in vivo; insight; lymph nodes; macrophage; monocyte; mortality; notch protein; novel therapeutics; pathogen; receptor; response; transcription factor; transcriptome sequencing

Infection with eukaryotic pathogens places an enormous burden on the health of many species including humans. Intracellular eukaryotic pathogens such as the dimorphic fungus, Histoplasma capsulatum (Hc), require a T helper (Th) 1 response to promote elimination. Th2 that produce interleukin (IL)-4 and IL-13 override the influence of Th1 and exaggerate the severity of infection to this fungus. While a Th2 response is detrimental to Hc and other intracellular pathogens, it is vital for clearance of helminths. Activation of Th1 or Th2 requires communication with dendritic cells (DCs). Knowledge regarding transcriptional regulators that license the latter to promote a Th1 or Th2 response is incomplete. We have discovered that the transcription factor, Krüppel-like factor (KLF) 2, in DCs calibrates the vigor of the Th2 response. A loss of KLF2 in DCs enhances release of IL-4 and IL-13 by Th2 and promotes accrual of these cells in lungs of Hc-infected mice. The net result is impaired clearance of the fungus. The enhanced release of type 2 cytokines is dependent on an expansion of DCs that express the Notch ligand, Jagged2. These preliminary data stimulated the central hypothesis that KLF2 is a key element in DCs that limits the magnitude of Th2 responses and thus, differentially regulates the severity of infection with Hc or with helminths. To test this hypothesis, we propose three Specific Aims. Aim 1 will elucidate how KLF2-deficient DCs promote Th2 immunity. Studies will examine: 1) the influence of KLF2 on conventional DCs in lungs and draining lymph nodes, 2) the impact on Th2 recruitment, survival, and/or proliferation and 3) the role of DC KLF2 in controlling infection with a helminth. Specific Aim 2 will shift the focus to T cells and examine the role of Notch receptors and Notch ligands on T cell function in Hc and helminth infection. Specific Aim 3 will explore the genomic landscape regulated by KLF2 with a focus on the transcription factor hypoxia inducing factor-1. In addition, we will open the aperture and perform RNA-seq and chromatin immunoprecipitation (ChIP)-Seq to identify the KLF2-dependent gene networks in DCs that regulate Notch signaling and Th2 accrual. A better understanding of the regulation of DCs by KLF2 during infection with intracellular and extracellular pathogens protective could lead to the development of new therapies that govern immunity to Hc and to helminths.

真核病原体的感染使许多物种的健康造成了巨大的伯宁 人类。细胞内真核病原体，例如二态真菌，组织囊肿（HC），需要 T助手（Th）1响应以促进消除。产生白介素（IL）-4和IL-13的Th2覆盖 TH1的影响并夸大了感染对这种真菌的严重程度。而TH2响应不利 HC和其他细胞内病原体，对于蠕虫的清除至关重要。 TH1或TH2的激活需要 与树突状细胞（DCS）通信。有关转录调节器的知识 促进Th1或Th2响应是不完整的。我们发现转录因子类似于krüppel DC中的因子（KLF）2校准了Th2响应的活力。 DC中KLF2的损失增强了IL-4的释放 由Th2和IL-13促进了HC感染小鼠的肺中这些细胞的负体。最终结果受损 清除真菌。 2型细胞因子的增强释放取决于DC的扩展 表达缺口配体，锯齿状2。这些初步数据刺激了KLF2是关键的中心假设 DC中的元素限制了Th2响应的幅度，因此对调节的严重程度有所不同 用HC或蠕虫感染。为了检验这一假设，我们提出了三个具体目标。 AIM 1将阐明 KLF2缺陷DC如何促进Th2免疫史。研究将检查：1）KLF2对常规的影响 肺中的DC和排水淋巴结，2）对Th2募集，生存和/或增殖的影响以及3） DC KLF2在控制蠕虫感染中的作用。特定的目标2将把焦点转移到T细胞，并且 检查Notch受体和缺口配体对HC和蠕虫感染中T细胞功能的作用。具体的 AIM 3将探索由KLF2调节的基因组景观，重点是转录因子缺氧 诱导因子1。此外，我们将打开光圈并执行RNA-seq和染色质 免疫沉淀（芯片）-Seq识别调节Notch的DC中KLF2依赖的基因网络 信号传导和TH2应计。更好地理解KLF2在感染期间对DC的调节 受保护的细胞内和细胞外病原体可能导致发展的新疗法 对HC和蠕虫的免疫力。