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

感染真核病原体给许多物种的健康带来了巨大的负担，包括 人类。细胞内真核病原体，如二相性真菌，组织胞浆菌(HC)，需要 促进消除的T辅助分子(Th)1反应。产生白介素4和白介素13的Th2细胞 Th1的影响，夸大了该真菌感染的严重程度。而Th2应答是有害的 HC和其他细胞内的病原体，对于清除蠕虫是至关重要的。激活Th1或Th2需要 与树突状细胞(DC)的通讯。关于许可后者的转录监管机构的知识 推动Th1或Th2反应是不完整的。我们发现转录因子Krüppel样蛋白 树突状细胞中的因子(KLF)2校准Th2反应的活力。树突状细胞KLF2缺失可促进IL-4的释放 和IL-13通过Th2，并促进这些细胞在HC感染的小鼠肺内的增加。最终结果是受损的 清除真菌。2型细胞因子的增强释放依赖于树突状细胞的扩张 表达Notch配体，Jagged2。这些初步数据刺激了核心假设，即KLF2是一个关键 树突状细胞中限制Th2反应大小的元件，从而以不同的方式调节疾病的严重性 感染丙型肝炎或蠕虫。为了检验这一假设，我们提出了三个具体目标。目标1将澄清 KLF2缺陷的DC如何促进Th2免疫。研究将检验：1)KLF2对传统 肺和引流淋巴结中的树突状细胞，2)对Th2募集、存活和/或增殖的影响和3) DC KLF2在控制蠕虫感染中的作用特定目标2将把焦点转移到T细胞和 研究Notch受体和Notch配体在HC和蠕虫感染中对T细胞功能的作用。特定的 目标3将探索KLF2调控的基因组格局，重点是转录因子低氧 诱导因子-1。此外，我们将打开光圈，进行rna-seq和染色质检测。 免疫沉淀(CHIP)-序列技术鉴定树突状细胞中调节Notch的KLF2依赖基因网络 信令和Th2的产生。更好地理解KLF2感染DCs时对DC的调节 细胞内和细胞外病原体的保护可能导致开发新的治疗方法 对HC和蠕虫免疫。

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.