Abstract
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.
Key points
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Tuft cells are key players in mucosal tissues, orchestrating type 2 immunity and other antimicrobial responses that facilitate rapid adaptation to luminal signals.
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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.
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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.
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The canonical taste signalling components GNAT3 (also known as Gαgus), PLCβ2, 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.
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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.
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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 Tritrichomonas protists in an interconnected network.
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References
von Moltke, J. in Physiology of the Gastrointestinal Tract 6th edn (ed. Hamid, M.) 721–733 (Academic, 2018).
Bezençon, C. et al. Murine intestinal cells expressing Trpm5 are mostly brush cells and express markers of neuronal and inflammatory cells. J. Comp. Neurol. 509, 514–525 (2008).
Gerbe, F. et al. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 529, 226–230 (2016).
von Moltke, J., Ji, M., Liang, H. E. & Locksley, R. M. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529, 221–225 (2016).
Howitt, M. R. et al. Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 351, 1329–1333 (2016).
O’Leary, C. E., Schneider, C. & Locksley, R. M. Tuft cells – systemically dispersed sensory epithelia integrating immune and neural circuitry. Annu. Rev. Immunol. 37, 47–72 (2019).
Schneider, C. Tuft cell integration of luminal states and interaction modules in tissues. Pflug. Arch. 473, 1713–1722 (2021).
Haber, A. L. et al. A single-cell survey of the small intestinal epithelium. Nature 551, 333–339 (2017).
Bornstein, C. et al. Single-cell mapping of the thymic stroma identifies IL-25-producing tuft epithelial cells. Nature 559, 622–626 (2018).
Nadjsombati, M. S. et al. Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit. Immunity 49, 33–41.e7 (2018).
Montoro, D. T. et al. A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature 560, 319–324 (2018).
Plasschaert, L. W. et al. A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte. Nature 560, 377–381 (2018).
Elmentaite, R. et al. Cells of the human intestinal tract mapped across space and time. Nature 597, 250–255 (2021).
Smillie, C. S. et al. Intra- and inter-cellular rewiring of the human colon during ulcerative colitis. Cell 178, 714–730.e22 (2019).
Burclaff, J. et al. A proximal-to-distal survey of healthy adult human small intestine and colon epithelium by single-cell transcriptomics. Cell Mol. Gastroenterol. Hepatol. 13, 1554–1589 (2022).
Billipp, T. E., Nadjsombati, M. S. & von Moltke, J. Tuning tuft cells: new ligands and effector functions reveal tissue-specific function. Curr. Opin. Immunol. 68, 98–106 (2021).
Schneider, C., O’Leary, C. E. & Locksley, R. M. Regulation of immune responses by tuft cells. Nat. Rev. Immunol. 19, 584–593 (2019).
Kotas, M. E., O’Leary, C. E. & Locksley, R. M. Tuft cells: context- and tissue-specific programming for a conserved cell lineage. Annu. Rev. Pathol. 18, 311–335 (2023).
Silverman, J. B., Vega, P. N., Tyska, M. J. & Lau, K. S. Intestinal tuft cells: morphology, function, and implications for human health. Annu. Rev. Physiol. 86, 479–504 (2024).
Gerbe, F., Legraverend, C. & Jay, P. The intestinal epithelium tuft cells: specification and function. Cell Mol. Life Sci. 69, 2907–2917 (2012).
van Es, J. H. et al. Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat. Cell Biol. 14, 1099–1104 (2012).
Gerbe, F. et al. Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium. J. Cell Biol. 192, 767–780 (2011).
Bjerknes, M. et al. Origin of the brush cell lineage in the mouse intestinal epithelium. Dev. Biol. 362, 194–218 (2012).
Yamashita, J., Ohmoto, M., Yamaguchi, T., Matsumoto, I. & Hirota, J. Skn-1a/Pou2f3 functions as a master regulator to generate Trpm5-expressing chemosensory cells in mice. PLoS ONE 12, e0189340 (2017).
Matsumoto, I., Ohmoto, M., Narukawa, M., Yoshihara, Y. & Abe, K. Skn-1a (Pou2f3) specifies taste receptor cell lineage. Nat. Neurosci. 14, 685–687 (2011).
Wu, X. S. et al. OCA-T1 and OCA-T2 are coactivators of POU2F3 in the tuft cell lineage. Nature 607, 169–175 (2022).
Szczepanski, A. P. et al. POU2AF2/C11orf53 functions as a coactivator of POU2F3 by maintaining chromatin accessibility and enhancer activity. Sci. Adv. 8, eabq2403 (2022).
Zhou, C., Huang, H., Wang, Y., Sendinc, E. & Shi, Y. Selective regulation of tuft cell-like small cell lung cancer by novel transcriptional co-activators C11orf53 and COLCA2. Cell Discov. 8, 112 (2022).
Nadjsombati, M. S. et al. Genetic mapping reveals Pou2af2/OCA-T1-dependent tuning of tuft cell differentiation and intestinal type 2 immunity. Sci. Immunol. 8, eade5019 (2023).
Huang, L. et al. Tuft cells act as regenerative stem cells in the human intestine. Preprint at bioRxiv https://doi.org/10.1101/2024.03.17.585165 (2024).
Zinina, V. V., Sauer, M., Nigmatullina, L., Kreim, N. & Soshnikova, N. TCF7L1 controls the differentiation of tuft cells in mouse small intestine. Cells 12, 1452 (2023).
Noah, T. K. & Shroyer, N. F. Notch in the intestine: regulation of homeostasis and pathogenesis. Annu. Rev. Physiol. 75, 263–288 (2013).
VanDussen, K. L. et al. Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells. Development 139, 488–497 (2012).
Herring, C. A. et al. Unsupervised trajectory analysis of single-cell RNA-seq and imaging data reveals alternative tuft cell origins in the gut. Cell Syst. 6, 37–51.e9 (2018).
Banerjee, A. et al. Succinate produced by intestinal microbes promotes specification of tuft cells to suppress ileal inflammation. Gastroenterology 159, 2101–2115.e5 (2020).
Gracz, A. D. et al. Sox4 promotes Atoh1-independent intestinal secretory differentiation toward tuft and enteroendocrine fates. Gastroenterology 155, 1508–1523.e10 (2018).
Coutry, N. et al. Cross talk between Paneth and tuft cells drives dysbiosis and inflammation in the gut mucosa. Proc. Natl Acad. Sci. USA 120, e2219431120 (2023).
Zhao, M. et al. Epithelial STAT6 O-GlcNAcylation drives a concerted anti-helminth alarmin response dependent on tuft cell hyperplasia and gasdermin C. Immunity 55, 623–638.e5 (2022).
Lindholm, H. T. et al. BMP signaling in the intestinal epithelium drives a critical feedback loop to restrain IL-13-driven tuft cell hyperplasia. Sci. Immunol. 7, eabl6543 (2022).
Lin, X. et al. IL-17RA-signaling in Lgr5+ intestinal stem cells induces expression of transcription factor ATOH1 to promote secretory cell lineage commitment. Immunity 55, 237–253.e8 (2022).
Xiong, Z. et al. Intestinal Tuft-2 cells exert antimicrobial immunity via sensing bacterial metabolite N-undecanoylglycine. Immunity 55, 686–700.e7 (2022).
Howitt, M. R. et al. The taste receptor TAS1R3 regulates small intestinal tuft cell homeostasis. Immunohorizons 4, 23–32 (2020).
Zhang, X. et al. Elevating EGFR-MAPK program by a nonconventional Cdc42 enhances intestinal epithelial survival and regeneration. JCI Insight 5, e135923 (2020).
Long, T. et al. RNA binding protein DDX5 directs tuft cell specification and function to regulate microbial repertoire and disease susceptibility in the intestine. Gut 71, 1790–1802 (2022).
Basak, O. et al. Induced quiescence of Lgr5+ stem cells in intestinal organoids enables differentiation of hormone-producing enteroendocrine cells. Cell Stem Cell 20, 177–190.e4 (2017).
Eshleman, E. M. et al. Microbiota-derived butyrate restricts tuft cell differentiation via histone deacetylase 3 to modulate intestinal type 2 immunity. Immunity 57, 319–332.e6 (2024).
Schumacher, M. A. et al. Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33. Nat. Commun. 12, 836 (2021).
Xiong, X. et al. Sirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity. Nat. Commun. 13, 5192 (2022).
Del Vecchio, A. et al. PCGF6 controls murine Tuft cell differentiation via H3K9me2 modification independently of Polycomb repression. Dev. Cell 59, 368–383.e7 (2024).
Manco, R. et al. Clump sequencing exposes the spatial expression programs of intestinal secretory cells. Nat. Commun. 12, 3074 (2021).
Miller, C. N. et al. Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development. Nature 559, 627–631 (2018).
Billipp, T. E. et al. Tuft cell-derived acetylcholine promotes epithelial chloride secretion and intestinal helminth clearance. Immunity 57, 1243–1259.e8 (2024).
Ndjim, M. et al. Tuft cell acetylcholine is released into the gut lumen to promote anti-helminth immunity. Immunity 57, 1260–1273.e7 (2024).
Schütz, B. et al. Chemical coding and chemosensory properties of cholinergic brush cells in the mouse gastrointestinal and biliary tract. Front. Physiol. 6, 87 (2015).
Zwick, R. K. et al. Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains. Nat. Cell Biol. 26, 250–262 (2024).
McKinley, E. T. et al. Optimized multiplex immunofluorescence single-cell analysis reveals tuft cell heterogeneity. JCI Insight 2, e93487 (2017).
Grunddal, K. V. et al. Adhesion receptor ADGRG2/GPR64 is in the GI-tract selectively expressed in mature intestinal tuft cells. Mol. Metab. 51, 101231 (2021).
Gehart, H. et al. Identification of enteroendocrine regulators by real-time single-cell differentiation mapping. Cell 176, 1158–1173.e16 (2019).
Ma, Z. et al. Single-cell transcriptomics reveals a conserved metaplasia program in pancreatic injury. Gastroenterology 162, 604–620.e20 (2022).
Barr, J. et al. Injury-induced pulmonary tuft cells are heterogenous, arise independent of key type 2 cytokines, and are dispensable for dysplastic repair. Elife 11, e78074 (2022).
Ualiyeva, S. et al. A nasal cell atlas reveals heterogeneity of tuft cells and their role in directing olfactory stem cell proliferation. Sci. Immunol. 9, eabq4341 (2024).
Roper, S. D. & Chaudhari, N. Taste buds: cells, signals and synapses. Nat. Rev. Neurosci. 18, 485–497 (2017).
Lei, W. et al. Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 immunity in the mouse small intestine. Proc. Natl Acad. Sci. USA 115, 5552–5557 (2018).
Schneider, C. et al. A metabolite-triggered tuft cell-ILC2 circuit drives small intestinal remodeling. Cell 174, 271–284.e14 (2018).
O’Leary, C. E., Feng, X., Cortez, V. S., Locksley, R. M. & Schneider, C. Interrogating the small intestine tuft cell–ILC2 circuit using in vivo manipulations. Curr. Protoc. 1, e77 (2021).
Perniss, A. et al. A succinate/SUCNR1-brush cell defense program in the tracheal epithelium. Sci. Adv. 9, eadg8842 (2023).
Luo, X. C. et al. Infection by the parasitic helminth Trichinella spiralis activates a Tas2r-mediated signaling pathway in intestinal tuft cells. Proc. Natl Acad. Sci. USA 116, 5564–5569 (2019).
Sun, S. et al. Oral berberine ameliorates high-fat diet-induced obesity by activating TAS2Rs in tuft and endocrine cells in the gut. Life Sci. 311, 121141 (2022).
Lei, H. et al. Tuft cells utilize taste signaling molecules to respond to the pathobiont microbe Ruminococcus gnavus in the proximal colon. Front. Immunol. 14, 1259521 (2023).
Kim, D. H. et al. A type 2 immune circuit in the stomach controls mammalian adaptation to dietary chitin. Science 381, 1092–1098 (2023).
Zhang, Z., Zhao, Z., Margolskee, R. & Liman, E. The transduction channel TRPM5 is gated by intracellular calcium in taste cells. J. Neurosci. 27, 5777–5786 (2007).
Hisatsune, C. et al. Abnormal taste perception in mice lacking the type 3 inositol 1,4,5-trisphosphate receptor. J. Biol. Chem. 282, 37225–37231 (2007).
Gao, N. et al. Voltage-gated sodium channels in taste bud cells. BMC Neurosci. 10, 20 (2009).
Taruno, A. et al. CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. Nature 495, 223–226 (2013).
Ma, Z. et al. CALHM3 is essential for rapid ion channel-mediated purinergic neurotransmission of GPCR-mediated tastes. Neuron 98, 547–561.e10 (2018).
Feng, X. et al. Tuft cell IL-17RB restrains IL-25 bioavailability and reveals context-dependent ILC2 hypoproliferation. Preprint at bioRxiv https://doi.org/10.1101/2024.03.04.583299 (2024).
Arige, V. et al. Functional determination of calcium-binding sites required for the activation of inositol 1,4,5-trisphosphate receptors. Proc. Natl Acad. Sci. USA 119, e2209267119 (2022).
Shindo, Y. et al. Lrmp/Jaw1 is expressed in sweet, bitter, and umami receptor-expressing cells. Chem. Senses 35, 171–177 (2010).
Chang, C. Y. et al. Tumor suppressor p53 regulates intestinal type 2 immunity. Nat. Commun. 12, 3371 (2021).
McGinty, J. W. et al. Tuft-cell-derived leukotrienes drive rapid anti-helminth immunity in the small intestine but are dispensable for anti-protist immunity. Immunity 52, 528–541.e7 (2020).
Wilson, S. C. et al. Organizing structural principles of the IL-17 ligand-receptor axis. Nature 609, 622–629 (2022).
Li, X., Bechara, R., Zhao, J., McGeachy, M. J. & Gaffen, S. L. IL-17 receptor-based signaling and implications for disease. Nat. Immunol. 20, 1594–1602 (2019).
Goswami, S. et al. Divergent functions for airway epithelial matrix metalloproteinase 7 and retinoic acid in experimental asthma. Nat. Immunol. 10, 496–503 (2009).
Lin, L. L., Lin, A. Y. & Knopf, J. L. Cytosolic phospholipase A2 is coupled to hormonally regulated release of arachidonic acid. Proc. Natl Acad. Sci. USA 89, 6147–6151 (1992).
Thulasingam, M. & Haeggstrom, J. Z. Integral membrane enzymes in eicosanoid metabolism: structures, mechanisms and inhibitor design. J. Mol. Biol. 432, 4999–5022 (2020).
von Moltke, J. et al. Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s. J. Exp. Med. 214, 27–37 (2017).
Keshavarz, M. et al. Cysteinyl leukotrienes and acetylcholine are biliary tuft cell cotransmitters. Sci. Immunol. 7, eabf6734 (2022).
Haeggstrom, J. Z. & Funk, C. D. Lipoxygenase and leukotriene pathways: biochemistry, biology, and roles in disease. Chem. Rev. 111, 5866–5898 (2011).
Haeggstrom, J. Z. Leukotriene biosynthetic enzymes as therapeutic targets. J. Clin. Invest. 128, 2680–2690 (2018).
DelGiorno, K. E. et al. Tuft cells inhibit pancreatic tumorigenesis in mice by producing prostaglandin D2. Gastroenterology 159, 1866–1881.e8 (2020).
Wojno, E. D. et al. The prostaglandin D2 receptor CRTH2 regulates accumulation of group 2 innate lymphoid cells in the inflamed lung. Mucosal Immunol. 8, 1313–1323 (2015).
Xue, L. et al. Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells. J. Allergy Clin. Immunol. 133, 1184–1194 (2014).
Chang, J. E., Doherty, T. A., Baum, R. & Broide, D. Prostaglandin D2 regulates human type 2 innate lymphoid cell chemotaxis. J. Allergy Clin. Immunol. 133, 899–901.e3 (2014).
Wambre, E. et al. A phenotypically and functionally distinct human TH2 cell subpopulation is associated with allergic disorders. Sci. Transl. Med. 9, eaam9171 (2017).
Oyesola, O. O. et al. PGD2 and CRTH2 counteract type 2 cytokine-elicited intestinal epithelial responses during helminth infection. J. Exp. Med. 218, e20202178 (2021).
Akiho, H., Blennerhassett, P., Deng, Y. & Collins, S. M. Role of IL-4, IL-13, and STAT6 in inflammation-induced hypercontractility of murine smooth muscle cells. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G226–G232 (2002).
Zhao, A. et al. Dependence of IL-4, IL-13, and nematode-induced alterations in murine small intestinal smooth muscle contractility on Stat6 and enteric nerves. J. Immunol. 171, 948–954 (2003).
Gustafsson, J. K. & Johansson, M. E. V. The role of goblet cells and mucus in intestinal homeostasis. Nat. Rev. Gastroenterol. Hepatol. 19, 785–803 (2022).
Middelhoff, M. et al. Prox1-positive cells monitor and sustain the murine intestinal epithelial cholinergic niche. Nat. Commun. 11, 111 (2020).
Beumer, J. & Clevers, H. Cell fate specification and differentiation in the adult mammalian intestine. Nat. Rev. Mol. Cell Biol. 22, 39–53 (2021).
Maizels, R. M. & Gause, W. C. Targeting helminths: the expanding world of type 2 immune effector mechanisms. J. Exp. Med. 220, e20221381 (2023).
Strine, M. S. & Wilen, C. B. Tuft cells are key mediators of interkingdom interactions at mucosal barrier surfaces. PLoS Pathog. 18, e1010318 (2022).
Xi, R. et al. Up-regulation of gasdermin C in mouse small intestine is associated with lytic cell death in enterocytes in worm-induced type 2 immunity. Proc. Natl Acad. Sci. USA 118, e2026307118 (2021).
Yang, L. et al. Intraepithelial mast cells drive gasdermin C-mediated type 2 immunity. Immunity 57, 1056–1070.e5 (2024).
Entwistle, L. J. et al. Epithelial-cell-derived phospholipase A2 group 1B is an endogenous anthelmintic. Cell Host Microbe 22, 484–493.e5 (2017).
Zheng, X. et al. Gingival solitary chemosensory cells are immune sentinels for periodontitis. Nat. Commun. 10, 4496 (2019).
Lee, R. J. et al. Bitter and sweet taste receptors regulate human upper respiratory innate immunity. J. Clin. Invest. 124, 1393–1405 (2014).
Fung, C. et al. Tuft cells mediate commensal remodeling of the small intestinal antimicrobial landscape. Proc. Natl Acad. Sci. USA 120, e2216908120 (2023).
Fricke, W. F. et al. Type 2 immunity-dependent reduction of segmented filamentous bacteria in mice infected with the helminthic parasite Nippostrongylus brasiliensis. Microbiome 3, 40 (2015).
Hu, Z. et al. Small proline-rich protein 2A is a gut bactericidal protein deployed during helminth infection. Science 374, eabe6723 (2021).
Yu, S. et al. Paneth cell-derived lysozyme defines the composition of mucolytic microbiota and the inflammatory tone of the intestine. Immunity 53, 398–416.e8 (2020).
Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).
Sonnenberg, G. F., Fouser, L. A. & Artis, D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat. Immunol. 12, 383–390 (2011).
Perez Escriva, P., Fuhrer, T. & Sauer, U. Distinct N and C cross-feeding networks in a synthetic mouse gut consortium. mSystems 7, e0148421 (2022).
Orchard, R. C. et al. Discovery of a proteinaceous cellular receptor for a norovirus. Science 353, 933–936 (2016).
Wilen, C. B. et al. Tropism for tuft cells determines immune promotion of norovirus pathogenesis. Science 360, 204–208 (2018).
Strine, M. S. et al. Tuft-cell-intrinsic and -extrinsic mediators of norovirus tropism regulate viral immunity. Cell Rep. 41, 111593 (2022).
Ingle, H. et al. IFN-λ derived from nonsusceptible enterocytes acts on tuft cells to limit persistent norovirus. Sci. Adv. 9, eadi2562 (2023).
Strine, M. S. et al. Intestinal tuft cell immune privilege enables norovirus persistence. Sci. Immunol. 9, eadi7038 (2024).
Bomidi, C., Robertson, M., Coarfa, C., Estes, M. K. & Blutt, S. E. Single-cell sequencing of rotavirus-infected intestinal epithelium reveals cell-type specific epithelial repair and tuft cell infection. Proc Natl Acad Sci USA 118, e2112814118 (2021).
Desai, P. et al. Enteric helminth coinfection enhances host susceptibility to neurotropic flaviviruses via a tuft cell-IL-4 receptor signaling axis. Cell 184, 1214–1231.e6 (2021).
Graziano, V. R. et al. CD300lf is the primary physiologic receptor of murine norovirus but not human norovirus. PLoS Pathog. 16, e1008242 (2020).
Gerrick, E. R. et al. Metabolic diversity in commensal protists regulates intestinal immunity and trans-kingdom competition. Cell 187, 62–78.e20 (2024).
Wei, Y. et al. Commensal bacteria impact a protozoan’s integration into the murine gut microbiota in a dietary nutrient-dependent manner. Appl. Environ. Microbiol. 86, e00303-20 (2020).
Popovic, A. et al. Commensal protist Tritrichomonas musculus exhibits a dynamic life cycle that induces extensive remodeling of the gut microbiota. ISME J 18, wrae023 (2024).
Westphalen, C. B. et al. Long-lived intestinal tuft cells serve as colon cancer-initiating cells. J. Clin. Invest. 124, 1283–1295 (2014).
Nakanishi, Y. et al. Dclk1 distinguishes between tumor and normal stem cells in the intestine. Nat. Genet. 45, 98–103 (2013).
Huang, Y. H. et al. POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer. Genes. Dev. 32, 915–928 (2018).
Goto, N. et al. Lineage tracing and targeting of IL17RB+ tuft cell-like human colorectal cancer stem cells. Proc. Natl Acad. Sci. USA 116, 12996–13005 (2019).
Jou, E. et al. An innate IL-25–ILC2–MDSC axis creates a cancer-permissive microenvironment for Apc mutation-driven intestinal tumorigenesis. Sci. Immunol. 7, eabn0175 (2022).
O’Keefe, R. N. et al. A tuft cell–ILC2 signaling circuit provides therapeutic targets to inhibit gastric metaplasia and tumor development. Nat. Commun. 14, 6872 (2023).
Hayakawa, Y. et al. Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling. Cancer Cell 31, 21–34 (2017).
Smith, K. A. et al. Concerted IL-25R and IL-4Rα signaling drive innate type 2 effector immunity for optimal helminth expulsion. Elife 7, e38269 (2018).
Campbell, L. et al. ILC2s mediate systemic innate protection by priming mucus production at distal mucosal sites. J. Exp. Med. 216, 2714–2723 (2019).
Munoz-Antoli, C. et al. Interleukin-25 induces resistance against intestinal trematodes. Sci. Rep. 6, 34142 (2016).
Alvarez-Izquierdo, M., Guillermo Esteban, J., Munoz-Antoli, C. & Toledo, R. Ileal proteomic changes associated with IL-25-mediated resistance against intestinal trematode infections. Parasit. Vectors 13, 336 (2020).
Buonomo, E. L. et al. Microbiota-regulated IL-25 increases eosinophil number to provide protection during Clostridium difficile infection. Cell Rep. 16, 432–443 (2016).
O’Leary, C. E. et al. Bile acid-sensitive tuft cells regulate biliary neutrophil influx. Sci. Immunol. 7, eabj1080 (2022).
Nevo, S. et al. Tuft cells and fibroblasts promote thymus regeneration through ILC2-mediated type 2 immune response. Sci. Immunol. 9, eabq6930 (2024).
Lucas, B. et al. Diversity in medullary thymic epithelial cells controls the activity and availability of iNKT cells. Nat. Commun. 11, 2198 (2020).
Tizzano, M. et al. Nasal chemosensory cells use bitter taste signaling to detect irritants and bacterial signals. Proc. Natl Acad. Sci. USA 107, 3210–3215 (2010).
Ualiyeva, S. et al. Airway brush cells generate cysteinyl leukotrienes through the ATP sensor P2Y2. Sci. Immunol. 5, eaax7224 (2020).
Krasteva, G., Canning, B. J., Papadakis, T. & Kummer, W. Cholinergic brush cells in the trachea mediate respiratory responses to quorum sensing molecules. Life Sci. 91, 992–996 (2012).
Bankova, L. G. et al. The cysteinyl leukotriene 3 receptor regulates expansion of IL-25-producing airway brush cells leading to type 2 inflammation. Sci. Immunol. 3, eaat9453 (2018).
Fu, Z., Ogura, T., Luo, W. & Lin, W. ATP and odor mixture activate TRPM5-expressing microvillous cells and potentially induce acetylcholine release to enhance supporting cell endocytosis in mouse main olfactory epithelium. Front. Cell Neurosci. 12, 71 (2018).
Perniss, A. et al. Chemosensory cell-derived acetylcholine drives tracheal mucociliary clearance in response to virulence-associated formyl peptides. Immunity 52, 683–699.e11 (2020).
Hollenhorst, M. I. et al. Tracheal brush cells release acetylcholine in response to bitter tastants for paracrine and autocrine signaling. FASEB J. 34, 316–332 (2020).
Hollenhorst, M. I. et al. Taste receptor activation in tracheal brush cells by denatonium modulates ENaC channels via Ca2+, cAMP and ACh. Cells 11, 2411 (2022).
Rane, C. K. et al. Development of solitary chemosensory cells in the distal lung after severe influenza injury. Am. J. Physiol. Lung Cell Mol. Physiol 316, L1141–L1149 (2019).
Melms, J. C. et al. A molecular single-cell lung atlas of lethal COVID-19. Nature 595, 114–119 (2021).
Deckmann, K. et al. Bitter triggers acetylcholine release from polymodal urethral chemosensory cells and bladder reflexes. Proc. Natl Acad. Sci. USA 111, 8287–8292 (2014).
Schmidt, P. et al. Tas1R3 dependent and independent recognition of sugars in the urethra and the role of tuft cells in this process. Adv. Biol. 8, e2400117 (2024).
Tallini, Y. N. et al. BAC transgenic mice express enhanced green fluorescent protein in central and peripheral cholinergic neurons. Physiol. Genomics 27, 391–397 (2006).
Gautron, L. et al. Neuronal and nonneuronal cholinergic structures in the mouse gastrointestinal tract and spleen. J. Comp. Neurol. 521, 3741–3767 (2013).
Krasteva, G. et al. Cholinergic chemosensory cells in the trachea regulate breathing. Proc. Natl Acad. Sci. USA 108, 9478–9483 (2011).
Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).
Schuijers, J., van der Flier, L. G., van Es, J. & Clevers, H. Robust Cre-mediated recombination in small intestinal stem cells utilizing the Olfm4 locus. Stem Cell Rep. 3, 234–241 (2014).
van der Flier, L. G. et al. Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell 136, 903–912 (2009).
Gehart, H. & Clevers, H. Tales from the crypt: new insights into intestinal stem cells. Nat. Rev. Gastroenterol. Hepatol. 16, 19–34 (2019).
Tian, H. et al. Opposing activities of Notch and Wnt signaling regulate intestinal stem cells and gut homeostasis. Cell Rep. 11, 33–42 (2015).
Flanagan, D. J. et al. Frizzled7 functions as a Wnt receptor in intestinal epithelial Lgr5+ stem cells. Stem Cell Rep. 4, 759–767 (2015).
Yang, Y. P. et al. A chimeric Egfr protein reporter mouse reveals Egfr localization and trafficking in vivo. Cell Rep. 19, 1257–1267 (2017).
Sangiorgi, E. & Capecchi, M. R. Bmi1 is expressed in vivo in intestinal stem cells. Nat. Genet. 40, 915–920 (2008).
Montgomery, R. K. et al. Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem clls. Proc. Natl Acad. Sci. USA 108, 179–184 (2011).
Takeda, N. et al. Interconversion between intestinal stem cell populations in distinct niches. Science 334, 1420–1424 (2011).
Powell, A. E. et al. The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell 149, 146–158 (2012).
Ishibashi, F. et al. Contribution of ATOH1+ cells to the homeostasis, repair, and tumorigenesis of the colonic epithelium. Stem Cell Rep. 10, 27–42 (2018).
Kim, T. H. et al. Single-cell transcript profiles reveal multilineage priming in early progenitors derived from Lgr5+ intestinal stem cells. Cell Rep. 16, 2053–2060 (2016).
van Es, J. H. et al. Notch/λ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435, 959–963 (2005).
Sancho, R., Cremona, C. A. & Behrens, A. Stem cell and progenitor fate in the mammalian intestine: Notch and lateral inhibition in homeostasis and disease. EMBO Rep. 16, 571–581 (2015).
Yang, Q., Bermingham, N. A., Finegold, M. J. & Zoghbi, H. Y. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294, 2155–2158 (2001).
VanDussen, K. L. & Samuelson, L. C. Mouse atonal homolog 1 directs intestinal progenitors to secretory cell rather than absorptive cell fate. Dev. Biol. 346, 215–223 (2010).
Clevers, H. The intestinal crypt, a prototype stem cell compartment. Cell 154, 274–284 (2013).
Krndija, D. et al. Active cell migration is critical for steady-state epithelial turnover in the gut. Science 365, 705–710 (2019).
Burclaff, J. & Mills, J. C. Plasticity of differentiated cells in wound repair and tumorigenesis, part II: skin and intestine. Dis. Model. Mech. 11, dmm035071 (2018).
Acknowledgements
The authors thank all members of the Schneider laboratory, J. von Moltke and M. R. Howitt for helpful discussions. C.S. is supported by grants from the Swiss National Science Foundation (Eccellenza grant 194216) and the Peter Hans Hofschneider Professorship for Molecular Medicine.
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All authors researched data for the article and made substantial contributions to discussion of the content. X.F., P.F. and C.S. contributed equally to writing and reviewing/editing the manuscript before submission.
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Glossary
- Bone morphogenetic protein
-
(BMP). Belonging to the superfamily of TGFβ, BMPs regulate epithelial stemness and differentiation patterning in the small intestine by forming an activity gradient along the crypt–villus axis.
- Cysteinyl leukotrienes
-
Leukotrienes C4, D4 and E4 are potent lipid mediators generated by oxidation of arachidonic acid released from membrane phospholipids and conjugated to glutathione, involving enzymes such as phospholipases, ALOX5 and LTC4S.
- Epidermal growth factor
-
(EGF). A common proliferation-inducing factor that exerts its actions through the EGF receptor tyrosine kinase, EGFR, important for intestinal stem cells.
- Helminths
-
Parasitic worms and widely prevalent macroparasites some of which live and reproduce in the host gastrointestinal tract; associated with stimulation of type 2 immune responses.
- IL-4 receptor-α
-
Cytokine receptor subunit required for the responses to IL-4 and IL-13.
- ILC2s
-
Group 2 innate lymphoid cells are innate sources of cytokines IL-5, IL-9 and IL-13 that are critical for early type 2 immune responses.
- Protists
-
Unicellular eukaryotic organisms; free-living or parasitic, such as flagellated parabasalid protists of the genus Tritrichomonas.
- Tuft cell core gene expression profiles
-
Transcriptional signature characteristic of tuft cells across all mucosal surfaces, including the transcripts for Pou2f3, Gfi1b, Il25 and Alox5.
- Tuft cell–ILC2 circuit
-
Cellular interaction module in the small intestine, enabled by tuft cell-derived IL-25 and ILC2-derived IL-13, and characterized by its feed-forward nature.
- Tuft-1 and tuft-2
-
Two transcriptional programmes observed in multiple tissues when clustering tuft cell single-cell RNA sequencing data; enriched for neuronal and immune transcripts.
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Feng, X., Flüchter, P., De Tenorio, J.C. et al. Tuft cells in the intestine, immunity and beyond. Nat Rev Gastroenterol Hepatol (2024). https://doi.org/10.1038/s41575-024-00978-1
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DOI: https://doi.org/10.1038/s41575-024-00978-1
