Developmental pathways regulate cytokine-driven effector and feedback responses in the intestinal epithelium

Lindholm, Håvard T.; Parmar, Naveen; Drurey, Claire; Ostrop, Jenny; Díez-Sanchez, Alberto; Maizels, Rick M.; Oudhoff, Menno J.

The intestinal tract is a common site for infection, and it relies on an appropriate immune response to defend against pathogens. The intestinal epithelium has an important role in effector responses, which is coordinated by immune-type specific cytokines. It is incompletely understood how cytokines drive epithelial responses. Here, using organoid-cytokine co-cultures, we provide a comprehensive analysis of how key cytokines affect the intestinal epithelium, and relate this to in vivo infection models. We use imaging, based on a convolutional neural network, and transcriptomic analysis to reveal that cytokines use developmental pathways to define intestinal epithelial effector responses. For example, we find IL-22 and IL-13 dichotomously induce goblet cells, in which only IL-13 driven goblet cells are associated with NOTCH signaling. We further show that IL-13 induces BMP signalling to act as a negative feedback loop in IL-13 induced tuft cell hyperplasia, an important aspect of type 2 immunity. Together, we show that targeting developmental pathways may be a useful tool to tailor epithelial effector responses that are necessary for immunity to infection.