Epithelial cells secrete chloride to regulate water release at mucosal barriers, supporting both homeostatic hydration and the “weep” response that is critical for type 2 immune defense against parasitic worms (helminths). Epithelial tuft cells in the small intestine sense helminths and release cytokines and lipids to activate type 2 immune cells, but whether they regulate epithelial secretion is unknown. Here, we found that tuft cell activation rapidly induced epithelial chloride secretion in the small intestine. This response required tuft cell sensory functions and tuft cell-derived acetylcholine (ACh), which acted directly on neighboring epithelial cells to stimulate chloride secretion, independent of neurons. Maximal tuft cell-induced chloride secretion coincided with immune restriction of helminths, and clearance was delayed in mice lacking tuft cell-derived ACh, despite normal type 2 inflammation. Thus, we have uncovered an epithelium-intrinsic response unit that uses ACh to couple tuft cell sensing to the secretory defenses of neighboring epithelial cells.

上皮细胞分泌氯化物来调节粘膜屏障处的水释放，支持稳态水合作用和“哭泣”反应，这对于针对寄生虫（蠕虫）的 2 型免疫防御至关重要。小肠中的上皮簇细胞感知蠕虫并释放细胞因子和脂质以激活 2 型免疫细胞，但它们是否调节上皮分泌尚不清楚。在这里，我们发现簇细胞激活迅速诱导小肠上皮氯分泌。这种反应需要簇细胞感觉功能和簇细胞衍生的乙酰胆碱（ACh），后者直接作用于邻近的上皮细胞，刺激氯离子分泌，不依赖于神经元。簇状细胞诱导的最大氯化物分泌与蠕虫的免疫限制同时发生，尽管存在正常的 2 型炎症，但在缺乏簇状细胞衍生的 ACh 的小鼠中，清除被延迟。因此，我们发现了一个上皮固有的反应单元，它使用乙酰胆碱将簇细胞感应与邻近上皮细胞的分泌防御耦合起来。