Tuft cells are epithelial sentinels that monitor the luminal environment at barrier sites throughout the body. Their function as crucial initiators of type 2 immunity against helminths and protists in the intestine emerged nearly a decade ago. Since then, key tuft cell mechanisms and effectors involved in anti-helminth immunity have been described, but their responses to a wider array of microbes, like viruses, remain far less understood. Here, we review the roles of tuft cells during both helminth and viral infections at barrier tissues like the lung and the gut. While tuft cells protect against parasite infections, they exhibit a wider and sometimes contradictory influence on viral infections and pathology. We explore the emerging and context-dependent role of tuft cells in antiviral responses and examine how tuft cells act as molecular switches during helminth-viral co-infections to dramatically alter infection outcomes.

The gut microbiota critically influences many aspects of host biology, from nutrient acquisition to immunological function, and is integral to metazoan life. While most microbiome research has focused on bacteria, the intestinal microbiota encompasses a diverse constellation of microorganisms, including viruses, fungi, archaea, and protists. Among these microbes, commensal protists have been particularly neglected, to the point that their status as true members of the microbiota remained contentious. However, findings over the past decade revealed that commensal protists, particularly those in the Parabasalia phylum (parabasalids), perform keystone roles within the intestinal ecosystem. Emerging evidence highlights how parabasalids dramatically impact host immunity, gut microbiome ecology, and host susceptibility to both infectious and inflammatory diseases. In this review, we discuss the recent discoveries of the varied and powerful roles of commensal parabasalids in the intestinal microbiota and outline the challenges and opportunities in this burgeoning new area of the microbiome field.

Epithelial cells secrete chloride to regulate water release at mucosal barriers, supporting both homeostatic hydration and the “weep” response that is critical for type 2 immune defense against parasitic worms (helminths). Epithelial tuft cells in the small intestine sense helminths and release cytokines and lipids to activate type 2 immune cells, but whether they regulate epithelial secretion is unknown. Here, we found that tuft cell activation rapidly induced epithelial chloride secretion in the small intestine. This response required tuft cell sensory functions and tuft cell-derived acetylcholine (ACh), which acted directly on neighboring epithelial cells to stimulate chloride secretion, independent of neurons. Maximal tuft cell-induced chloride secretion coincided with immune restriction of helminths, and clearance was delayed in mice lacking tuft cell-derived ACh, despite normal type 2 inflammation. Thus, we have uncovered an epithelium-intrinsic response unit that uses ACh to couple tuft cell sensing to the secretory defenses of neighboring epithelial cells.

The persistent murine norovirus strain MNV CR6 is a model for human norovirus and enteric viral persistence. MNV CR6 causes chronic infection by directly infecting intestinal tuft cells, rare chemosensory epithelial cells. Although MNV CR6 induces functional MNV-specific CD8 + T cells, these lymphocytes fail to clear infection. To examine how tuft cells promote immune escape, we interrogated tuft cell interactions with CD8 + T cells by adoptively transferring JEDI (just EGFP death inducing) CD8 + T cells into Gfi1b-GFP tuft cell reporter mice. Unexpectedly, some intestinal tuft cells partially resisted JEDI CD8 + T cell–mediated killing—unlike Lgr5 + intestinal stem cells and extraintestinal tuft cells—despite seemingly normal antigen presentation. When targeting intestinal tuft cells, JEDI CD8 + T cells predominantly adopted a T resident memory phenotype with decreased effector and cytotoxic capacity, enabling tuft cell survival. JEDI CD8 + T cells neither cleared nor prevented MNV CR6 infection in the colon, the site of viral persistence, despite targeting a virus-independent antigen. Ultimately, we show that intestinal tuft cells are relatively resistant to CD8 + T cells independent of norovirus infection, representing an immune-privileged niche that can be leveraged by enteric microbes.

The memory CD8+ T cell pool contains phenotypically and transcriptionally heterogeneous subsets with specialized functions and recirculation patterns. Here, we examined the epigenetic landscape of CD8+ T cells isolated from seven non-lymphoid organs across four distinct infection models, alongside their circulating T cell counterparts. Using single-cell transposase-accessible chromatin sequencing (scATAC-seq), we found that tissue-resident memory T (TRM) cells and circulating memory T (TCIRC) cells develop along distinct epigenetic trajectories. We identified organ-specific transcriptional regulators of TRM cell development, including FOSB, FOS, FOSL1, and BACH2, and defined an epigenetic signature common to TRM cells across organs. Finally, we found that although terminal TEX cells share accessible regulatory elements with TRM cells, they are defined by TEX-specific epigenetic features absent from TRM cells. Together, this comprehensive data resource shows that TRM cell development is accompanied by dynamic transcriptome alterations and chromatin accessibility changes that direct tissue-adapted and functionally distinct T cell states.

SummaryThe microbiota influences intestinal health and physiology, yet the contributions of commensal protists to the gut environment have been largely overlooked. Here, we identified several new rodent- and human-associated parabasalid protists. Genomic and metabolomic analyses of murine parabasalids from the genusTritrichomonasrevealed species-level differences in the excretion of the metabolite succinate. This metabolic dissimilarity results in distinct small intestinal immune responses during protist colonization. Metabolic differences betweenTritrichomonasspecies also determine their ecological niche within the microbiota. By manipulating dietary fibers and developingin vitroprotist culture, we show that different parabasalid species preferentially rely on dietary polysaccharides or mucus glycans. These polysaccharide preferences create trans-kingdom competition with specific commensal bacteria, which affects intestinal immunity in a diet-dependent manner. Our findings reveal unappreciated diversity in commensal parabasalids, elucidate differences in commensal protist metabolism, and suggest how dietary interventions could regulate their impact on gut health.

Schistosomiasis affects nearly 240 million people in predominately low- and middle-income countries and ranks second in the number of cases and socio-economic burden among all parasitic diseases. Despite the enormous burden posed by schistosomes, our understanding of how schistosomiasis impacts infected human tissues remains limited. Intestinal schistosomiasis in animal models leads to goblet cell hyperplasia, likely increasing mucus production and reflecting an intestinal type 2 immune response. However, it is unknown whether these same changes occur in schistosome-infected humans. Using immunofluorescence and light microscopy, we compared the abundance and morphology of goblet cells in patients diagnosed with schistosomiasis to uninfected controls. The mucin-containing vesicles in goblet cells from schistosome-infected patients were significantly larger (hypertrophic) than uninfected individuals, although goblet cell hyperplasia was absent in chronic human schistosomiasis. In addition, we examined tuft cells in the large intestinal epithelium of control and schistosome-infected patients. Tuft cell numbers expand during helminth infection in mice, but these cells have not been characterized in human parasite infections. We found no evidence of tuft cell hyperplasia during human schistosome infection. Thus, our study provides novel insight into schistosome-associated changes to the intestinal epithelium in humans, suggesting an increase in mucus production by large intestinal goblet cells but relatively minor effects on tuft cell numbers.

Tuft cells are solitary chemosensory epithelial cells that can sense lumenal stimuli at mucosal barriers and secrete effector molecules to regulate the physiology and immune state of their surrounding tissue. In the small intestine, tuft cells detect parasitic worms (helminths) and microbe-derived succinate, and signal to immune cells to trigger a Type 2 immune response that leads to extensive epithelial remodeling spanning several days. Acetylcholine (ACh) from airway tuft cells has been shown to stimulate acute changes in breathing and mucocilliary clearance, but its function in the intestine is unknown. Here we show that tuft cell chemosensing in the intestine leads to release of ACh, but that this does not contribute to immune cell activation or associated tissue remodeling. Instead, tuft cell-derived ACh triggers immediate fluid secretion from neighboring epithelial cells into the intestinal lumen. This tuft cell-regulated fluid secretion is amplified during Type 2 inflammation, and helminth clearance is delayed in mice lacking tuft cell ACh. The coupling of the chemosensory function of tuft cells with fluid secretion creates an epithelium-intrinsic response unit that effects a physiological change within seconds of activation. This response mechanism is shared by tuft cells across tissues, and serves to regulate the epithelial secretion that is both a hallmark of Type 2 immunity and an essential component of homeostatic maintenance at mucosal barriers.

Parabasalid protists recently emerged as keystone members of the mammalian microbiota with important effects on their host's health. However, the prevalence and diversity of parabasalids in wild reptiles and the consequences of captivity and other environmental factors on these symbiotic protists are unknown. Reptiles are ectothermic, and their microbiomes are subject to temperature fluctuations, such as those driven by climate change. Thus, conservation efforts for threatened reptile species may benefit from understanding how shifts in temperature and captive breeding influence the microbiota, including parabasalids, to impact host fitness and disease susceptibility. Here, we surveyed intestinal parabasalids in a cohort of wild reptiles across three continents and compared these to captive animals. Reptiles harbor surprisingly few species of parabasalids compared to mammals, but these protists exhibited a flexible host-range, suggesting specific adaptations to reptilian social structures and microbiota transmission. Furthermore, reptile-associated parabasalids are adapted to wide temperature ranges, although colder temperatures significantly altered the protist transcriptomes, with increased expression of genes associated with detrimental interactions with the host. Our findings establish that parabasalids are widely distributed in the microbiota of wild and captive reptiles and highlight how these protists respond to temperature swings encountered in their ectothermic hosts.

Succinate produced by the commensal protist Tritrichomonas musculis (T. mu) stimulates chemosensory tuft cells, resulting in intestinal type 2 immunity. Tuft cells express the succinate receptor SUCNR1, yet this receptor does not mediate antihelminth immunity nor alter protist colonization. Here, we report that microbial-derived succinate increases Paneth cell numbers and profoundly alters the antimicrobial peptide (AMP) landscape in the small intestine. Succinate was sufficient to drive this epithelial remodeling, but not in mice lacking tuft cell chemosensory components required to detect this metabolite. Tuft cells respond to succinate by stimulating type 2 immunity, leading to interleukin-13-mediated epithelial and AMP expression changes. Moreover, type 2 immunity decreases the total number of mucosa-associated bacteria and alters the small intestinal microbiota composition. Finally, tuft cells can detect short-term bacterial dysbiosis that leads to a spike in luminal succinate levels and modulate AMP production in response. These findings demonstrate that a single metabolite produced by commensals can markedly shift the intestinal AMP profile and suggest that tuft cells utilize SUCNR1 and succinate sensing to modulate bacterial homeostasis.

Food allergies have steadily increased worldwide and can cause life-threatening anaphylactic reactions. In the United States, hospital visits by children due to food allergies doubled from 2000 to 2009,1Rudders S.A. Arias S.A. Camargo C.A. Trends in hospitalizations for food-induced anaphylaxis in US children, 2000-2009.J Allergy Clin Immunol. 2014; 134: 960-963Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar with similar trends in Europe and Australia.2Turner P.J. Campbell D.E. Motosue M.S. Campbell R.L. Global trends in anaphylaxis epidemiology and clinical implications.J Allergy Clin Immunol Pract. 2020; 8: 1169-1176Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar This rapid increase implicates lifestyle and environmental changes, including shifts in diet, the microbiota, and exposure to environmental chemicals as drivers of the rising incidence of allergy. Notably, food allergies have increased across many communities with diverse cultural traditions, diets, and medical practices; thus, a confluence of multiple factors likely leads to allergic sensitization. The pathophysiology of food allergies is closely linked to type 2 immunity and recognition of allergens by IgE. However, the concentration of food-specific IgE antibodies in serum does not predict the severity of food anaphylaxis,3Fleischer D.M. Bock S.A. Spears G.C. Wilson C.G. Miyazawa N.K. Gleason M.C. et al.Oral food challenges in children with a diagnosis of food allergy.J Pediatr. 2011; 158: 578-583.e1Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar suggesting that factors beyond antibody recognition of food antigens alter the severity and sensitivity of food allergies. One such factor could be a subset of chemosensory intestinal epithelial cells called tuft cells, which initiate type 2 immunity in response to various luminal signals. This article will discuss how tuft cells may contribute to food allergies and the potential for microbial and environmental perturbations to increase succinate in the gut and induce tuft cell activation (Fig 1). Tuft cells orchestrate antiparasitic immunity in the gut by releasing effector molecules, including IL-25, to recruit and activate group 2 innate lymphocyte cells (ILC2s). In turn, ILC2s release IL-13 to promote differentiation of additional tuft cells from epithelial progenitor cells, thereby engaging a feed-forward loop to amplify intestinal type 2 immunity.4O'Leary C.E. Schneider C. Locksley R.M. Tuft cells—systemically dispersed sensory epithelia integrating immune and neural circuitry.Annu Rev Immunol. 2018; 37: 47-72Crossref Scopus (75) Google Scholar Although tuft cell–associated type 2 immunity is best understood from research on their response to parasites and other intestinal microbes, several studies have begun to suggest roles for tuft cells in allergic reactions. Tuft cells in the airway respond to complex aeroallergens, such as the house dust mite Dermatophagoides pteronyssinus (Dp) and the mold Alternaria, by releasing proinflammatory lipids called cysteinyl leukotrienes.5Ualiyeva S. Hallen N. Kanaoka Y. Ledderose C. Matsumoto I. Junger W.G. et al.Airway brush cells generate cysteinyl leukotrienes through the ATP sensor P2Y2.Sci Immunol. 2020; 5eaax7224Crossref PubMed Scopus (50) Google Scholar Interestingly, this study found that tuft cells use the purinergic receptor P2Y2 to detect ATP and UTP, which may be released in response to cell damage. Because food allergens often interact with host cell lipids and damage membranes, we speculate that intestinal tuft cells could also use receptors to detect food allergen–associated cell damage and potentiate allergic sensitization. Leyva-Castillo et al6Leyva-Castillo J.-M. Galand C. Kam C. Burton O. Gurish M. Musser M.A. et al.Mechanical skin injury promotes food anaphylaxis by driving intestinal mast cell expansion.Immunity. 2019; 50: 1262-1264Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar revealed a direct role for tuft cells in food anaphylaxis while investigating mechanisms responsible for the strong association between atopic dermatitis and food allergies.6Leyva-Castillo J.-M. Galand C. Kam C. Burton O. Gurish M. Musser M.A. et al.Mechanical skin injury promotes food anaphylaxis by driving intestinal mast cell expansion.Immunity. 2019; 50: 1262-1264Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar Tape stripping the skin of mice causes mechanical damage that mimics scratching common with patients with atopic dermatitis and results in IL-33 release by skin keratinocytes. This cytokine enters the bloodstream and synergizes with IL-25 derived from intestinal tuft cells to stimulate IL-13 production by ILC2s. The increase in IL-13 drives the differentiation of more IL-25–producing tuft cells, thereby engaging the previously observed tuft cell–ILC2 feed-forward loop. Increased IL-13 production also promotes intestinal mast cell accumulation, allowing these cells to bind IgE and increase gut permeability. When mice were concurrently subjected to oral antigen challenge and tape stripping, they experienced more severe anaphylaxis than mice without mechanical skin injury. However, if mice lacked tuft cell–derived IL-25, tape stripping failed to increase intestinal mast cell numbers in the intestine, which reduced the severity of food anaphylaxis. This study established a skin-gut connection in food allergies and demonstrated a direct role of tuft cells in this process. Tuft cells may contribute to the passage of allergens across the epithelial barrier by promoting secretory-antigen passages (SAPs) in the small intestine. At steady state, goblet cell–associated luminal passages allow dendritic cells in the lamina propria to acquire luminal contents and promote tolerance. However, ILC2-derived IL-13 drives secretory cells, including goblet, Paneth, and enteroendocrine cells to form SAPs that allow food allergens to cross the epithelial barrier and contact IgE and mast cells.7Noah T.K. Knoop K.A. McDonald K.G. Gustafsson J.K. Waggoner L. Vanoni S. et al.IL-13-induced intestinal secretory epithelial cell antigen passages are required for IgE-mediated food-induced anaphylaxis.J Allergy Clin Immunol. 2019; 144: 1058-1073.e3Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Because tuft cell activation leads to increased IL-13 and goblet cell hyperplasia, stimulation of tuft cells by signals in the gut lumen may promote food allergy by inducing SAP formation. Tuft cells express a myriad of G protein–coupled receptors that signal through the taste chemosensory pathway to trigger type 2 immunity. Loss of key components of the taste signal transduction pathway, such as TRPM5, significantly blunt the response of tuft cells to microbial signals.4O'Leary C.E. Schneider C. Locksley R.M. Tuft cells—systemically dispersed sensory epithelia integrating immune and neural circuitry.Annu Rev Immunol. 2018; 37: 47-72Crossref Scopus (75) Google Scholar RNA-sequencing analysis of murine tuft cells from different anatomical sites revealed a heterogeneous assortment of G protein–coupled receptors and lineage-specific identities, with the succinate receptor particularly enriched in Atoh-1–independent tuft cells from the distal small intestine.8Nadjsombati M.S. McGinty J.W. Lyons-Cohen M.R. Pollack J.L. Nagana Gowda G.A. Erle D.J. et al.Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit.Immunity. 2018; 49: 1-42Abstract Full Text Full Text PDF Scopus (260) Google Scholar,9Banerjee A. Herring C.A. Chen B. Kim H. Simmons A.J. Southard-Smith A.N. et al.Succinate produced by intestinal microbes promotes specification of Tuft cells to suppress ileal inflammation.Gastroenterology. 2020; 159: 2101-2115Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Consistent with this observation, feeding mice succinate in their drinking water was sufficient to activate tuft cells and trigger type 2 immunity in the ileum.8Nadjsombati M.S. McGinty J.W. Lyons-Cohen M.R. Pollack J.L. Nagana Gowda G.A. Erle D.J. et al.Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit.Immunity. 2018; 49: 1-42Abstract Full Text Full Text PDF Scopus (260) Google Scholar Because food allergy sensitization, intestinal permeability, and localized inflammatory amplification occur predominately in the jejunum and ileum, succinate may contribute to the sensitivity and severity of food allergies through activation of tuft cells in this region of the gut. The host and microbiota are both potential sources of intestinal succinate because mammalian cells produce succinate as an intermediate metabolite in the tricarboxylic acid cycle, and microbial fermentation can excrete succinate as a metabolic by-product. At homeostasis, intestinal succinate is below the concentration required to activate tuft cells and type 2 immunity. However, oral laxatives and antibiotics such as streptomycin disrupt the microbiota to transiently increase local succinate concentrations and activate tuft cell–mediated type 2 immunity.4O'Leary C.E. Schneider C. Locksley R.M. Tuft cells—systemically dispersed sensory epithelia integrating immune and neural circuitry.Annu Rev Immunol. 2018; 37: 47-72Crossref Scopus (75) Google Scholar We hypothesize that some modern medications may create short-term microbiota dysbiosis that shifts the metabolic balance in the distal small intestine to favor succinate producers over succinate-consuming bacteria. Moreover, changes to the microbiota may damage host cells, thereby releasing additional succinate into the intestinal compartment. These microbial disturbances may co-occur with other factors to increase the sensitivity or severity of food allergies. In addition to succinate derived from mammalian and microbial metabolism, the modern environment may directly contribute to elevated levels of succinate in the gut. Disodium succinate is a widely used flavor enhancer in savory foods, including canned seafood, instant noodles, and processed meat.10Pais C. Franco-Duarte R. Sampaio P. Wildner W. Carolas A. Figueira D. et al.Chapter 9-Production of dicarboxylic acid platform chemicals using yeasts: focus on succinic acid, biotransformation of agricultural waste and by-products.in: Poltronieri P. Fernando O. the food, feed, fiber, fuel (4F) economy. Amsterdam: Elsevier, Biotransformation of agricultural waste and by-products in the 4F Economy2016: 237-269Google Scholar Furthermore, succinate is a component of several biodegradable plastic products, such as grocery bags, drinking cups, and planter boxes, and it is used as a pharmaceutical stabilizer.10Pais C. Franco-Duarte R. Sampaio P. Wildner W. Carolas A. Figueira D. et al.Chapter 9-Production of dicarboxylic acid platform chemicals using yeasts: focus on succinic acid, biotransformation of agricultural waste and by-products.in: Poltronieri P. Fernando O. the food, feed, fiber, fuel (4F) economy. Amsterdam: Elsevier, Biotransformation of agricultural waste and by-products in the 4F Economy2016: 237-269Google Scholar Although neither processed foods nor chemical synthesis has been directly shown to increase intestinal succinate levels, they illustrate the potential of an industrialized environment to activate tuft cells in the gut, thus possibly priming food allergy. Intestinal tuft cells detect microbial signals and initiate a type 2 immune response, but their role in food allergy has been less clear. Yet, recent findings suggest potential mechanisms by which tuft cells may detect allergen-associated damage, promote mast cell activation, and enhance the passage of food allergens across the epithelial barrier. Succinate activates tuft cells in the distal small intestine of mice and may reduce the threshold for allergic reactions to foods. Several changes to the modern environment and lifestyle may increase intestinal concentrations of succinate, although the role of this metabolite in food allergies awaits further experimental and clinical investigations.

Tuft cells are specialized taste-chemosensory cells that detect the presence of intestinal parasites and orchestrate type 2 immunity. In this issue of Immunity, McGinty et al. discover that parasitic worms, but not commensal protists, stimulate tuft cells to release cysteinyl leukotrienes to amplify anti-helminth immunity in the small intestine.

Tuft cells are an epithelial cell type critical for initiating type 2 immune responses to parasites and protozoa in the small intestine. To respond to these stimuli, intestinal tuft cells use taste chemosensory signaling pathways, but the role of taste receptors in type 2 immunity is poorly understood. In this study, we show that the taste receptor TAS1R3, which detects sweet and umami in the tongue, also regulates tuft cell responses in the distal small intestine. BALB/c mice, which have an inactive form of TAS1R3, as well as Tas1r3-deficient C57BL6/J mice both have severely impaired responses to tuft cell–inducing signals in the ileum, including the protozoa Tritrichomonas muris and succinate. In contrast, TAS1R3 is not required to mount an immune response to the helminth Heligmosomoides polygyrus, which infects the proximal small intestine. Examination of uninfected Tas1r3−/− mice revealed a modest reduction in the number of tuft cells in the proximal small intestine but a severe decrease in the distal small intestine at homeostasis. Together, these results suggest that TAS1R3 influences intestinal immunity by shaping the epithelial cell landscape at steady-state.

Complex interactions between host immunity and the microbiome regulate norovirus infection. However, the mechanism of host immune promotion of enteric virus infection remains obscure. The cellular tropism of noroviruses is also unknown. Recently, we identified CD300lf as a murine norovirus (MNoV) receptor. In this study, we have shown that tuft cells, a rare type of intestinal epithelial cell, express CD300lf and are the target cell for MNoV in the mouse intestine. We found that type 2 cytokines, which induce tuft cell proliferation, promote MNoV infection in vivo. These cytokines can replace the effect of commensal microbiota in promoting virus infection. Our work thus provides insight into how the immune system and microbes can coordinately promote enteric viral infection.

Intestinal epithelial cells absorb nutrients, respond to microbes, function as a barrier and help to coordinate immune responses. Here we report profiling of 53,193 individual epithelial cells from the small intestine and organoids of mice, which enabled the identification and characterization of previously unknown subtypes of intestinal epithelial cell and their gene signatures. We found unexpected diversity in hormone-secreting enteroendocrine cells and constructed the taxonomy of newly identified subtypes, and distinguished between two subtypes of tuft cell, one of which expresses the epithelial cytokine Tslp and the pan-immune marker CD45, which was not previously associated with non-haematopoietic cells. We also characterized the ways in which cell-intrinsic states and the proportions of different cell types respond to bacterial and helminth infections: Salmonella infection caused an increase in the abundance of Paneth cells and enterocytes, and broad activation of an antimicrobial program; Heligmosomoides polygyrus caused an increase in the abundance of goblet and tuft cells. Our survey highlights previously unidentified markers and programs, associates sensory molecules with cell types, and uncovers principles of gut homeostasis and response to pathogens.

The intestinal epithelium forms an essential barrier between a host and its microbiota. Protozoa and helminths are members of the gut microbiota of mammals, including humans, yet the many ways that gut epithelial cells orchestrate responses to these eukaryotes remain unclear. Here we show that tuft cells, which are taste-chemosensory epithelial cells, accumulate during parasite colonization and infection. Disruption of chemosensory signaling through the loss of TRMP5 abrogates the expansion of tuft cells, goblet cells, eosinophils, and type 2 innate lymphoid cells during parasite colonization. Tuft cells are the primary source of the parasite-induced cytokine interleukin-25, which indirectly induces tuft cell expansion by promoting interleukin-13 production by innate lymphoid cells. Our results identify intestinal tuft cells as critical sentinels in the gut epithelium that promote type 2 immunity in response to intestinal parasites.