Intestinal tuft cells are critical for anti-helminth parasite immunity because they produce IL-25, which triggers IL-13 secretion by activated group 2 innate lymphoid cells (ILC2s) to expand both goblet and tuft cells. We show that epithelial Elp3, a tRNA-modifying enzyme, promotes tuft cell differentiation and is consequently critical for IL-25 production, ILC2 activation, goblet cell expansion and control of Nippostrongylus brasiliensis helminth infection in mice. Elp3 is essential for the generation of intestinal immature tuft cells and for the IL-13-dependent induction of glycolytic enzymes such as Hexokinase 1 and Aldolase A. Importantly, loss of epithelial Elp3 in the intestine blocks the codon-dependent translation of the Gator1 subunit Nprl2, an mTORC1 inhibitor, which consequently enhances mTORC1 activation and stabilizes Atf4 in progenitor cells. Likewise, Atf4 overexpression in mouse intestinal epithelium blocks tuft cell differentiation in response to intestinal helminth infection. Collectively, our data define Atf4 as a negative regulator of tuft cells and provide insights into promotion of intestinal type 2 immune response to parasites through tRNA modifications.

中文翻译：

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Elp3 的缺失会通过 mTORC1-Atf4 轴阻碍肠簇细胞分化。


肠道簇细胞对于抗蠕虫寄生虫免疫至关重要，因为它们会产生 IL-25，而 IL-25 会触发激活的第 2 组先天淋巴细胞 (ILC2) 分泌 IL-13，从而扩大杯状细胞和簇细胞。我们发现，上皮 Elp3（一种 tRNA 修饰酶）可促进簇细胞分化，因此对于小鼠体内 IL-25 的产生、ILC2 激活、杯状细胞扩增和控制巴西圆线虫蠕虫感染至关重要。 Elp3 对于肠道未成熟簇细胞的生成以及 IL-13 依赖性糖酵解酶（如己糖激酶 1 和醛缩酶 A）的诱导至关重要。重要的是，肠道中上皮 Elp3 的丢失会阻止 Gator1 亚基的密码子依赖性翻译Nprl2 是一种 mTORC1 抑制剂，可增强 mTORC1 激活并稳定祖细胞中的 Atf4。同样，小鼠肠上皮细胞中 Atf4 的过度表达会阻碍肠道蠕虫感染引起的簇细胞分化。总的来说，我们的数据将 Atf4 定义为簇细胞的负调节因子，并为通过 tRNA 修饰促进肠道对寄生虫的 2 型免疫反应提供了见解。