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

Abstract

Intestinal parasite infections or allergic reactions promote IL-13–induced differentiation of tuft cells as one manifestation of type 2 immunity in the gut. Using organoid cultures of intestinal epithelial cells, Lindholm et al. investigated how the lymphocyte cytokines IL-13, IL-22, and IFNγ regulate the signaling pathways that influence epithelial differentiation. While tuft cell IL-25 promoted expansion of IL-13–producing ILC2s in a feed-forward loop, the resulting IL-13 also induced ligands of the bone morphogenetic protein (BMP) signaling pathway. BMP agonists acted on stem cells to prevent runaway tuft cell expansion by limiting expression of Sox4, a transcription factor required for tuft cell differentiation. These findings provide new molecular insights into how intestinal epithelial differentiation is carefully choreographed in response to a diverse array of cytokine signals.