The taste receptor TAS1R3 regulates small intestinal tuft cell homeostasis

Tuft cells are an epithelial cell subset critical for initiating type 2 immune responses to parasites and protozoa in the small intestine. To respond to these stimuli, intestinal tuft cells use taste chemosensory signaling pathways, but the role of taste receptors in type 2 immunity is poorly understood. Here, we show that the taste receptor TAS1R3, which detects sweet and umami in the tongue, also regulates tuft cell responses in the distal small intestine. BALB/c mice, which have an inactive form of TAS1R3, as well as Tas1r3-deficient C57BL6/J mice both have severely impaired responses to tuft cell-inducing signals in the ileum including the protozoa Tritrichomonas muris and succinate. In contrast, TAS1R3 is not required to mount an immune response to the helminth Heligmosomoides polygyrus, which infects the proximal small intestine. Examination of uninfected Tas1r3-/- mice revealed a modest reduction in the number of tuft cells in the proximal small intestine but a severe decrease in the distal small intestine at homeostasis. Together, these results suggest that TAS1R3 influences intestinal immunity by shaping the epithelial cell landscape at steady state. 6 replicates of Ileal tuft cells from C57BL/6J mice簇细胞（tuft cell）是一类上皮细胞亚群，在小肠内启动针对寄生虫与原生生物的2型免疫应答过程中发挥关键作用。肠道簇细胞依赖味觉化学感受信号通路响应上述刺激，但目前味觉受体在2型免疫中的功能仍有待深入阐明。本研究发现，在舌部可感知甜味与鲜味的味觉受体TAS1R3，同样能够调控远端小肠内的簇细胞应答。携带失活性TAS1R3的BALB/c小鼠，以及Tas1r3基因敲除的C57BL/6J小鼠，其回肠内针对簇细胞诱导信号（包括原生生物Tritrichomonas muris与琥珀酸盐）的应答均出现严重受损。与之相对，TAS1R3并非宿主针对感染近端小肠的蠕虫Heligmosomoides polygyrus产生免疫应答所必需的因子。对未感染状态下的Tas1r3基因敲除小鼠进行检测后发现，其近端小肠内的簇细胞数量仅出现轻度减少，但稳态下远端小肠的簇细胞数量则显著降低。综合上述结果，本研究提示TAS1R3可通过塑造稳态下的上皮细胞图谱，对肠道免疫功能产生调控作用。本数据集包含来自C57BL/6J小鼠回肠簇细胞的6份生物学重复样本。