Tuft cell-mediated pathogen sensing and inflammation resolution

Tuft cells are a rare type of epithelial cells characterized not only by their tuft-like structure but also by the expression of specific genes, including those encoding the transcription factor Pou2f3 and canonical gustatory signaling proteins. However, tuft cells can be heterogeneous in various features, both across different tissues and within the same tissue. Homeostatic tuft cells are generated from stem/progenitor cells; however, their formation and gene expression profiles are regulated epigenetically and in response to changes in their microenvironments. Ectopic formation of tuft cells, their transdifferentiation into other cell types, and dedifferentiation to stem/progenitor cells have also been found in some tissues upon severe injuries. Tuft cells function as chemosensory sentinels and can detect a variety of pathogens such as bacteria, protists, and helminths with their cell surface receptors. Activation of these receptors in turn activates intracellular signaling cascades, leading to the release of output effectors: the cytokine IL-25, the eicosanoids, and the transmitters acetyl choline and ATP, some of which act on group 2 innate lymphoid cells, triggering innate immune responses, or on neighboring epithelial cells to accelerate cilia beating and increase mucus secretion, or on the nerve terminals to initiate neuroimmune responses. Some tuft cells are also critical to inflammation resolution and tissue repair-an important part of the healing and recovery process. Further elucidation of tuft cells' ligands, respective receptors and downstream signaling pathways, and output effectors can provide more insights into these cells' pivotal roles in health and disease.