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.

真核病原体的感染对许多物种的健康造成巨大负担， 人类胞内真核病原体，如二型真菌，荚膜组织胞浆菌（Hc），需要 辅助性T细胞（Th）1应答，以促进消除。产生白细胞介素（IL）-4和IL-13的Th 2细胞覆盖了 Th 1的影响，加重了对该真菌的感染程度。虽然Th 2应答对 HC和其他细胞内病原体，它是至关重要的清除蠕虫。Th 1或Th 2的激活需要 与树突状细胞（DC）的通信。关于许可后者的转录调节因子的知识 促进Th 1或Th 2反应是不完整的。我们已经发现，转录因子，Krüppel样 因子（KLF）2校准Th 2应答的活力。DCs中KLF 2的缺失增强IL-4的释放 和IL-13，并促进这些细胞在HC感染小鼠的肺中的积累。净结果是受损的 清除真菌。2型细胞因子释放的增强依赖于DC的扩增， 表达Notch配体Jagged 2。这些初步数据刺激了核心假设，即KLF 2是一个关键的 DCs中限制Th 2应答幅度的元件，因此差异调节 感染Hc或蠕虫。为了验证这一假设，我们提出了三个具体目标。目标1将阐明 KLF 2缺陷型DC如何促进Th 2免疫研究将审查：1）KLF 2对传统的影响 肺和引流淋巴结中的DC，2）对Th 2募集、存活和/或增殖的影响，和3） DC KLF 2在控制蠕虫感染中的作用。具体目标2将把重点转移到T细胞， 检测Notch受体和Notch配体在HC和蠕虫感染中对T细胞功能的作用。具体 目的3将探索KLF 2调控的基因组景观，重点是转录因子缺氧 诱导因子-1此外，我们将打开光圈，进行RNA-seq和染色质 免疫沉淀（ChIP）-Seq鉴定DCs中调节Notch的KLF 2依赖性基因网络 信号传导和Th 2积累。更好地理解KLF 2在感染过程中对DCs的调节， 细胞内和细胞外病原体的保护可能会导致新的治疗方法的发展， 对HC和蠕虫免疫。