Tuft cell effector functions in the small intestine

项目总结/摘要 蠕虫、过敏原和某些原生生物都能刺激2型免疫反应， 全球疾病负担。目前，全球有超过10亿人感染蠕虫， 过敏性疾病发病率的上升代表了一种新兴的流行病。感知和信号事件 启动2型免疫的细胞仍然知之甚少，但在小肠中，它们需要上皮簇细胞。 簇细胞调节簇细胞来源的IL-25激活第2组先天淋巴样细胞的簇细胞-ILC 2回路 （ILC 2）在下面的组织。ILC 2分泌典型的2型细胞因子IL-5、-9和-13， 共同驱动2型免疫的标志，如嗜酸性粒细胞增多和组织重塑。IL-13也 通过诱导簇状细胞和杯状细胞增生促进前馈反应。毛丛的免疫功能 细胞需要化学感受途径，最近的研究确定微生物代谢物琥珀酸是一种 肠簇细胞配体，其足以激活簇-ILC 2回路。因此，簇细胞作为IL-25- 分泌免疫哨兵，但有几条证据支持这一提议的中心假设， 必须存在另外的簇细胞效应器功能：（1）簇细胞组成性地表达IL-25，但前馈效应器不表达IL-25。 tuft-ILC 2回路仅在蠕虫或原生生物存在时被激活，这表明额外的激活 信号;（2）免疫感应发生后簇细胞增生的启动表明簇细胞 有助于2型免疫的效应阶段;和（3）蠕虫清除在簇状细胞中更延迟， 缺乏IL-25的小鼠比仅缺乏IL-25的小鼠更高。因此，本提案的目标是发现和 表征小肠中新的簇状细胞效应子功能。使用创新的体外 试验和转基因小鼠品系的体内蠕虫感染，我们建议测试调节 以及簇细胞来源的IL-25、白三烯C4和乙酰胆碱的功能。这些研究应确定新的 蠕虫感染和过敏性疾病的治疗干预目标。

Project Summary/Abstract Helminths, allergens, and certain protists all stimulate a type 2 immune response and contribute significantly to the global disease burden. Currently, more than 1 billion individuals worldwide are infected with helminths, and the rising incidence of allergic disease represents an emerging epidemic. The sensing and signaling events that initiate type 2 immunity remain poorly understood, but in the small intestine they require epithelial tuft cells. Tuft cells regulate a tuft-ILC2 circuit in which tuft cell-derived IL-25 activates group 2 innate lymphoid cells (ILC2s) in the underlying tissue. ILC2s secrete the canonical type 2 cytokines IL-5, -9, and -13, which collectively drive hallmarks of type 2 immunity, such as eosinophilia and tissue remodeling. IL-13 also promotes a feed-forward response by inducing tuft and goblet cell hyperplasia. The immune function of tuft cells requires a chemosensory pathway and recent studies identified the microbial metabolite succinate as an intestinal tuft cell ligand that is sufficient to activate the tuft-ILC2 circuit. Tuft cells therefore act as IL-25- secreting immune sentinels, but several lines of evidence support the central hypothesis of this proposal that additional tuft cell effector functions must exist: (1) Tuft cells express IL-25 constitutively, but the feed-forward tuft-ILC2 circuit is only activated in the presence of helminths or protists, suggesting additional activating signals; (2) the initiation of tuft cell hyperplasia after immune sensing has occurred suggests tuft cells contribute to the effector stages of type 2 immunity; and (3) helminth clearance is more delayed in tuft cell- deficient mice than in mice that lack only IL-25. The goal of this proposal is therefore to discover and characterize novel tuft cell effector functions in the small intestine. Using a combination of innovative in vitro assays and in vivo helminth infection of genetically modified mouse strains, we propose to test the regulation and function of tuft cell-derived IL-25, leukotriene C4, and acetylcholine. These studies should identify novel targets for therapeutic intervention in both helminth infection and allergic disease.