Tuft cells in the intestine, immunity and beyond

Tuft cells have gained substantial attention over the past 10 years due to numerous reports linking them with type 2 immunity and microorganism-sensing capacity in many mucosal tissues. This heightened interest is fuelled by their unique ability to produce an array of biological effector molecules, including IL-25, allergy-related eicosanoids, and the neurotransmitter acetylcholine, enabling downstream responses in diverse cell types. Operating through G protein-coupled receptor-mediated signalling pathways reminiscent of type II taste cells in oral taste buds, tuft cells emerge as chemosensory sentinels that integrate luminal conditions, eliciting appropriate responses in immune, epithelial and neuronal populations. How tuft cells promote tissue alterations and adaptation to the variety of stimuli at mucosal surfaces has been explored in multiple studies in the past few years. Since the initial recognition of the role of tuft cells, the discovery of diverse tuft cell effector functions and associated feedback loops have also revealed the complexity of tuft cell biology. Although earlier work largely focused on extraintestinal tissues, novel genetic tools and recent mechanistic studies on intestinal tuft cells established fundamental concepts of tuft cell activation and functions. This Review is an overview of intestinal tuft cells, providing insights into their development, signalling and interaction modules in immunity and other states. Tuft cells have important roles in type 2 immunity and antimicrobial responses in mucosal tissues. This Review provides an overview of intestinal tuft cells, providing insights into their phenotype, function and role in the intestine in immunity and other states. Tuft cells are key players in mucosal tissues, orchestrating type 2 immunity and other antimicrobial responses that facilitate rapid adaptation to luminal signals.Tuft cell differentiation is influenced by diverse extrinsic cues, including microbial metabolites, cytokines and typical intestinal crypt niche signals, possibly contributing to their heterogeneous gene expression programmes.Stimulated by specific ligands, small intestinal tuft cells generate a tailored output, selecting from their known repertoire of effector molecules consisting of IL-25, leukotrienes, prostaglandin D2 and acetylcholine.The canonical taste signalling components GNAT3 (also known as G alpha gus), PLC beta 2, IP3R2, Ca2+ flux and TRPM5 are now established as essential in intestinal tuft cells for connecting the input succinate-SUCNR1 to the output IL-25.Tuft cells act as initiators and responders, enabling two-way communication with epithelial and immune cells, and generating feedback loops with some of the effector molecules.A central rheostat role for luminal succinate is emerging, positioning responsive tuft cells together with Paneth cells and their antimicrobial repertoires, microbiome composition, dietary fibres and protists in an interconnected network.