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

基本信息

批准号：
9195249
负责人：
GEORGE S. DEEPE
金额：
$ 51.27万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
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/9195249
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 Embryonic Development Equilibrium Eukaryota Evolution Family Genes Genomics Health Helminths Helper-Inducer T-Lymphocyte Histoplasma capsulatum Host resistance Human Hypoxia ITGAX gene Immune response Immune system Immunity Indium Infection Infection Control 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 Pathway interactions Phenotype Population Process Production Property 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

项目摘要

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.

真核病原体感染给许多物种的健康带来巨大负担，包括人类细胞内真核病原体，如二形性真菌、荚膜组织胞浆菌 (Hc)，需要 T 辅助细胞 (Th) 1 反应促进消除，产生白细胞介素 (IL)-4 和 IL-13。 Th1 的影响并夸大了这种真菌感染的严重程度，而 Th2 的反应则令人痛苦。 Hc 和其他细胞内病原体，对于清除蠕虫至关重要，需要激活 Th1 或 Th2。与树突状细胞 (DC) 的通讯有关授权后者的转录调节因子的知识。我们发现，Krüppel 样转录因子促进 Th1 或 Th2 反应是不完全的。 DC 中的因子 (KLF) 2 可校准 Th2 反应的强度 DC 中 KLF2 的缺失会增强 IL-4 的释放。 Th2 和 IL-13 并促进 Hc 感染小鼠肺部这些细胞的积累。最终结果受到损害。 2 型细胞因子释放的增强取决于 DC 的扩增。这些初步数据激发了 KLF2 是关键的中心假设。 DC 中限制 Th2 反应幅度的元素，从而差异化调节为了检验这一假设，我们提出三个具体目标 1 来阐明。 KLF2 缺陷的 DC 如何促进 Th2 免疫研究将检查：1) KLF2 对常规的影响。肺部和引流淋巴结中的 DC，2) 对 Th2 募集、存活和/或增殖的影响，以及 3) DC KLF2 在控制蠕虫感染中的作用特定目标 2 将焦点转移到 T 细胞和检查 Notch 受体和 Notch 配体对 Hc 和特定蠕虫感染中 T 细胞功能的作用。目标 3 将探索 KLF2 调控的基因组景观，重点关注转录因子缺氧诱导因子-1 此外，我们将打开孔径并进行RNA-seq和染色质。免疫沉淀 (ChIP)-Seq 用于识别 DC 中调节 Notch 的 KLF2 依赖性基因网络更好地了解 KLF2 在感染过程中对 DC 的调节。细胞内和细胞外病原体的保护可能会导致新疗法的开发对 Hc 和蠕虫的免疫力。