Gentile, M. E.; Maiden, M.; Singh, M.; Martinez, E.; Kelam, H.; Holcomb, N. P.; Wong, J.; Mendoza, M.; Abraham, D.; Klochkova, A.; Kass Gergi, S.; Vaughan, A. E.

Tuft cells act as sentinels that amplify type 2 inflammation primarily by activating type 2 innate lymphoid cells (ILC2s). Although normally absent from the distal lung, ectopic tuft cells form after severe lung injury including influenza infection in mice. Here, we investigated the function of these ectopic tuft cells in shaping innate immunity following influenza injury. We observed that IFN gamma; restrains tuft cell differentiation, whereas ILC2s drive tuft cell expansion, establishing a reciprocal regulatory axis. Tuft cell deficient mice exhibited reduced eosinophilic inflammation and expansion of ILC1s and ILC3s after influenza injury resolution. Single cell RNA seq of influenza infected whole lung revealed transcriptional signatures consistent with type 1 pathway activation, type 2 suppression and oxidative stress. Following influenza injury and subsequent Alternaria alternata challenge, tuft cell deficient mice also showed neutrophilic and ILC3 expansion. Together, these data identify a distal-airway tuft-cell ILC2 circuit that helps maintain a balanced inflammatory environment in response to viral injury and aeroallergens.