The intestinal tract is a common site for various types of infections including viruses, bacteria, and helminths, each requiring specific modes of immune defense. The intestinal epithelium has a pivotal role in both immune initiation and effector stages, which are coordinated by lymphocyte cytokines such as IFNγ, IL-13, and IL-22. Here, we studied intestinal epithelial immune responses using organoid image analysis based on a convolutional neural network, transcriptomic analysis, and in vivo infection models. We found that IL-13 and IL-22 both induce genes associated with goblet cells, but the resulting goblet cell phenotypes are dichotomous. Moreover, only IL-13–driven goblet cells are associated with classical NOTCH signaling. We further showed that IL-13 induces the bone morphogenetic protein (BMP) pathway, which acts in a negative feedback loop on immune type 2–driven tuft cell hyperplasia. This is associated with inhibiting Sox4 expression to putatively limit the tuft cell progenitor population. Blocking ALK2, a BMP receptor, with the inhibitor dorsomorphin homolog 1 (DMH1) interrupted the feedback loop, resulting in greater tuft cell numbers both in vitro and in vivo after infection with Nippostrongylus brasiliensis . Together, this investigation of cytokine effector responses revealed an unexpected and critical role for the BMP pathway in regulating type 2 immunity, which can be exploited to tailor epithelial immune responses.

中文翻译：

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肠上皮中的 BMP 信号驱动一个关键的反馈回路来抑制 IL-13 驱动的簇状细胞增生

肠道是各种感染的常见部位，包括病毒、细菌和蠕虫，每种感染都需要特定的免疫防御模式。肠上皮细胞在免疫启动和效应阶段都具有关键作用，这些阶段由淋巴细胞因子如 IFNγ、IL-13 和 IL-22 协调。在这里，我们使用基于卷积神经网络、转录组学分析和体内感染模型的类器官图像分析研究了肠上皮免疫反应。我们发现 IL-13 和 IL-22 都诱导与杯状细胞相关的基因，但由此产生的杯状细胞表型是二分的。此外，只有 IL-13 驱动的杯状细胞与经典的 NOTCH 信号相关。我们进一步表明 IL-13 诱导骨形态发生蛋白 (BMP) 通路，它在免疫 2 型驱动的簇绒细胞增生的负反馈回路中起作用。这与抑制有关Sox4推定地限制簇绒细胞祖细胞群的表达。用抑制剂 dorsomorphin 同系物 1 (DMH1) 阻断 BMP 受体 ALK2 会中断反馈回路，导致感染后体外和体内的簇绒细胞数量增加巴西日本圆线虫. 总之，这项对细胞因子效应反应的调查揭示了 BMP 通路在调节 2 型免疫方面的意想不到的关键作用，可用于定制上皮免疫反应。