BMP-signaling in the intestinal epithelium drives a critical feedback loop to restrain IL-13-driven tuft cell hyperplasia

The intestinal tract is a common site for different 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 immune-type specific cytokines such as IFNγ, IL-13 and IL-22. Here, we study intestinal epithelial immune responses using organoid image analysis based on a convolutional neural network, transcriptomic analysis, and in vivo infection models. We find that IL-22 and IL-13 both induce genes associated with goblet cells, but their phenotypes are dichotomous. Moreover, only IL-13 driven goblet cells are associated with classical NOTCH signaling. We further show that IL-13 induces BMP signaling, which acts in a negative feedback loop in immune type 2 driven tuft cell hyperplasia. This is associated with inhibiting Sox4 expression to putatively limit the tuft progenitor population. Blocking BMP signaling with the ALK2 inhibitor DMH1 interrupts the feedback loop, resulting in greater tuft cell numbers both in vitro and in vivo after infection with Nippostrongylus brasiliensis. Taken together, these novel aspects of cytokine effector responses reveal an unexpected and critical role for BMP signaling in type 2 immunity, which can be exploited to tailor epithelial immune responses.