Regulation of the tuft-ILC2 circuit in the small intestine

项目摘要 寄生虫(蠕虫)目前感染10-20亿人，是大范围发病的原因。 家畜蠕虫感染造成巨大的经济损失。与此同时，过敏的发生率是 在全球范围内增加，但特别是在没有蠕虫的地区。尽管看起来毫无关联， 蠕虫和过敏原在免疫上是联系在一起的，因为它们都能诱导2型免疫反应。这个 2型免疫的激活和调节仍不完全清楚，尤其是在小肠。 (四)。我们最近发现，抗蠕虫免疫需要罕见的化学感觉上皮绒毛细胞。 在SI中。簇状细胞激活第二组固有淋巴样细胞(ILC2s)，而ILC2s继而分泌规范的2型 协调2型免疫的细胞因子，如嗜酸性粒细胞增多症和组织重塑。具体来说， 上皮祖细胞中的IL-13信号使其对簇状细胞的谱系承诺发生偏差，导致簇状细胞的形成 在蠕虫感染期间和在原生滴虫定植的小鼠中的增殖。这种簇状ILC2电路是 当丛生细胞感觉到滴虫分泌的琥珀酸时激活，但配体和受体介导 蠕虫感应仍然是未知的。此外，虽然TUFT-ILC2电路的细胞和细胞间信号 正在出现，调节电路的细胞内信号通路仍然完全未知， 尤其是在上皮内。在这个方案中，我们研究了POU2F3是如何被调控来诱导簇状细胞的 增殖(目标1)，测试KIT信号在簇状细胞中的功能(目标2)，并表征新的簇状细胞 配体及其激活的细胞内信号(目标3)。除了蠕虫感染，TUFT-ILC2回路 最近被认为与肠道病毒感染和细菌失调引起的回肠炎有关。因此， 该项目揭示的调控机制有望确定治疗高血压的靶点。 大量的SI病理。

Project Summary Parasitic worms (helminths) currently infect 1-2 billion humans and are the cause of widespread morbidity. Helminth infections of livestock result in large economic losses. Meanwhile, the incidence of allergies is increasing globally, but particularly in regions where helminths are absent. Although seemingly unrelated, helminths and allergens are immunologically linked as they both induce a type 2 immune response. The activation and regulation of type 2 immunity remain incompletely understood, especially in the small intestine (SI). We recently discovered that rare chemosensory epithelial tuft cells are required for anti-helminth immunity in the SI. Tuft cells activate group 2 innate lymphoid cells (ILC2s), which in turn secrete canonical type 2 cytokines to coordinate hallmarks of type 2 immunity, such as eosinophilia and tissue remodeling. Specifically, IL-13 signaling in epithelial progenitors biases their lineage commitment towards tuft cells, leading to tuft cell hyperplasia during helminth infection and in mice colonized with Tritrichomonas protists. This tuft-ILC2 circuit is activated when tuft cells sense succinate secreted by Tritrichomonas, but the ligand and receptor mediating helminth sensing remain unknown. Additionally, while the cells and intercellular signals of the tuft-ILC2 circuit are emerging, the intracellular signaling pathways that regulate the circuit remain completely unknown, especially within the epithelium. In this proposal, we examine how POU2F3 is regulated to induce tuft cell hyperplasia (Aim 1), test the function of KIT signaling in tuft cells (Aim 2), and characterize novel tuft cell ligands and the intracellular signals they activate (Aim 3). In addition to helminth infection, the tuft-ILC2 circuit has recently been implicated in enteric virus infection and ileitis induced by bacterial dysbiosis. Therefore, the regulatory mechanisms uncovered by this project promise to identify therapeutic targets for the treatment of numerous SI pathologies.