Tuft cell effector functions in the small intestine

项目摘要/摘要 蠕虫、过敏原和某些原生生物都能刺激2型免疫反应，并对 全球疾病负担。目前，全球有超过10亿人感染了蠕虫， 过敏性疾病发病率的上升代表了一种新的流行病。感测和信令事件 启动2型免疫的机制仍然知之甚少，但在小肠中，它们需要上皮丛细胞。 丛生细胞调节丛生细胞衍生的IL-25激活第二组固有淋巴样细胞的簇状细胞-ILC2回路 (ILC2s)。ILC2分泌典型的2型细胞因子IL-5、-9和-13，它们 共同驱动2型免疫的特征，如嗜酸性粒细胞增多和组织重塑。IL-13也 通过诱导簇状和杯状细胞增生来促进前馈反应。绒毛的免疫功能 细胞需要一条化学感觉途径，最近的研究发现，微生物代谢产物琥珀酸是一种 肠绒毛细胞配体，足以激活TUFT-ILC2环路。因此，簇状细胞扮演着IL-25的角色。 分泌免疫哨兵，但有几条证据支持这一提议的中心假设 必须存在额外的簇状细胞效应功能：(1)簇状细胞结构性地表达IL-25，但前馈 TUFT-ILC2回路只有在蠕虫或原生生物存在的情况下才被激活，这意味着额外的激活 信号；(2)免疫感应发生后簇状细胞开始增殖，提示簇状细胞 有助于2型免疫的效应器阶段；以及(3)绒毛细胞中蠕虫的清除更延迟。 与只缺乏IL-25的小鼠相比，缺乏IL-25的小鼠更容易受到影响。因此，这项提议的目标是发现和 描述小肠中新的簇状细胞效应器的功能。在体外使用创新的组合 检测和体内感染转基因小鼠的蠕虫，我们建议测试这一调节 以及丛生细胞衍生的IL-25、白三烯C4和乙酰胆碱的功能。这些研究应该确定小说 蠕虫感染和过敏性疾病治疗干预的目标。

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.