Influenza-induced tuft cell expansion is associated with changes in ILC2 populations in the distal lungs of mice

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 IFNγ deficiency was associated with an increase in tuft cell and ILC2 expansion, whereas ILC2 deficiency was associated with reduced tuft cell expansion, consistent with a reciprocal regulatory axis. Tuft cell-deficient mice exhibited 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 and oxidative stress in the tuft cell-deficient mice. Following influenza injury and subsequent Alternaria alternata challenge, tuft cell-deficient mice also showed neutrophilic and ILC3 expansion. Together, these data are consistent with the presence of a distal-airway tuft-cell-ILC2 circuit that may help shape inflammatory responses to viral injury and aeroallergens.