Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit.
Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit.
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DOI：
10.1038/nature16161
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发表时间：
2016-01-14
期刊：
影响因子：
64.8
通讯作者：
Locksley RM
中科院分区：
文献类型：
--
作者：
von Moltke J;Ji M;Liang HE;Locksley RM
寄生蠕虫和过敏原诱导2型免疫应答，导致组织生理学的深刻变化，包括分泌粘液的杯状细胞的增生和平滑肌过度收缩。这种反应，称为“哭泣和清扫”，需要由组织驻留的第2组先天淋巴细胞（ILC2）和招募的2型辅助T细胞（TH2细胞）产生白细胞介素（IL）-13。在小鼠和人类中的实验已经证明了在ILC2的活化中需要上皮细胞因子IL-33、胸腺基质淋巴细胞生成素（TSLP）和IL-25，但是这些信号的来源和调节仍然不清楚。在小肠中，上皮由至少五种不同的细胞谱系组成，包括簇状细胞，其功能尚不清楚。在这里，我们表明，簇细胞组成型表达IL-25，以维持ILC2在小鼠固有层的静止稳态。蠕虫感染后，簇细胞来源的IL-25进一步激活ILC2分泌IL-13，IL-13作用于上皮隐窝祖细胞，促进簇细胞和杯状细胞的分化，导致两者的频率增加。因此，簇细胞、ILC2和上皮祖细胞构成了一个应答回路，该回路介导与小肠中的2型免疫相关的上皮重塑，并且可能在由这些细胞占据的其他粘膜屏障处。
Parasitic helminths and allergens induce a type 2 immune response leading to profound changes in tissue physiology, including hyperplasia of mucus-secreting goblet cells and smooth muscle hypercontractility. This response, known as ‘weep and sweep’, requires interleukin (IL)-13 production by tissue-resident group 2 innate lymphoid cells (ILC2s) and recruited type 2 helper T cells (TH2 cells). Experiments in mice and humans have demonstrated requirements for the epithelial cytokines IL-33, thymic stromal lymphopoietin (TSLP) and IL-25 in the activation of ILC2s, but the sources and regulation of these signals remain poorly defined. In the small intestine, the epithelium consists of at least five distinct cellular lineages, including the tuft cell, whose function is unclear. Here we show that tuft cells constitutively express IL-25 to sustain ILC2 homeostasis in the resting lamina propria in mice. After helminth infection, tuft-cell-derived IL-25 further activates ILC2s to secrete IL-13, which acts on epithelial crypt progenitors to promote differentiation of tuft and goblet cells, leading to increased frequencies of both. Tuft cells, ILC2s and epithelial progenitors therefore comprise a response circuit that mediates epithelial remodelling associated with type 2 immunity in the small intestine, and perhaps at other mucosal barriers populated by these cells.