Tuft cells restrain intestinal type 2 immunity through the transcription factor Spi-B

Excessive type 2 immunity underlies various disease conditions, including allergies, yet the homeostatic mechanisms that limit type 2 responses are not fully understood. Here, we revealed that intestinal tuft cells, specialized epithelial cells known for triggering type 2 immune activation, also have a molecular circuit that restrains type 2 responses. Ablation of the transcription factor Spi-B in tuft cells was sufficient to elicit spontaneous type 2 inflammation. Tuft cell-intrinsic deficiency of Spi-B rendered otherwise resistant C57BL/6J mice susceptible to food allergy models. Spi-B repressed c-Kit signaling-driven production of the type 2 alarmin TSLP by tuft cells. Disruption of this negative regulatory axis led to tuft cell hyperplasia and exacerbated type 2 inflammation, which could be pharmacologically targeted with a tyrosine kinase inhibitor. These findings pinpoint a crucial tuft cell-centric checkpoint of type 2 immunity and highlight the dual role of tuft cells in both promoting and restraining type 2 responses.