Tuning tuft cells: new ligands and effector functions reveal tissue-specific function

Billipp, Tyler E.; Nadjsombati, Marija S.; Moltke, Jakob von

doi:10.1016/j.coi.2020.09.006

Cited by 47 publications

(37 citation statements)

References 58 publications

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“…These drive the “weep and sweep” response with increased epithelial mucus production and intestinal muscular contractility required for parasite expulsion, and expansion of epithelial goblet, Paneth, and tuft cells ( Gerbe et al, 2016 ; Howitt et al, 2016 ; Kamal et al, 2002 ; Sharpe et al, 2018 ). Recently, tuft cells have been recognized as central orchestrators in this response, producing IL-25, leukotrienes, and other mediators that activate ILC2s to produce IL-13 ( Billipp et al, 2021 ; McGinty et al, 2020 ; von Moltke et al, 2016 ). IL-13 stimulates epithelial cells in a positive feedback loop to increase tuft and goblet cell numbers.…”

Section: Introductionmentioning

confidence: 99%

Intestinal epithelial tuft cell induction is negated by a murine helminth and its secreted products

Drurey

Lindholm

Coakley

et al. 2021

Journal of Experimental Medicine

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Helminth parasites are adept manipulators of the immune system, using multiple strategies to evade the host type 2 response. In the intestinal niche, the epithelium is crucial for initiating type 2 immunity via tuft cells, which together with goblet cells expand dramatically in response to the type 2 cytokines IL-4 and IL-13. However, it is not known whether helminths modulate these epithelial cell populations. In vitro, using small intestinal organoids, we found that excretory/secretory products (HpES) from Heligmosomoides polygyrus blocked the effects of IL-4/13, inhibiting tuft and goblet cell gene expression and expansion, and inducing spheroid growth characteristic of fetal epithelium and homeostatic repair. Similar outcomes were seen in organoids exposed to parasite larvae. In vivo, H. polygyrus infection inhibited tuft cell responses to heterologous Nippostrongylus brasiliensis infection or succinate, and HpES also reduced succinate-stimulated tuft cell expansion. Our results demonstrate that helminth parasites reshape their intestinal environment in a novel strategy for undermining the host protective response.

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Section: Introductionmentioning

confidence: 99%

Intestinal epithelial tuft cell induction is negated by a murine helminth and its secreted products

Drurey

Lindholm

Coakley

et al. 2021

Journal of Experimental Medicine

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“…Activated ILC2 secretes Th2 cytokines, such as IL-13 and IL-4, and promotes the hyperplasia of both tuft and goblet cells, leading to the mucous secretion and activation of intestinal motility, known as the “weep and sweep” response [ 5 ]. Other physiological functions of tuft cells in the gut are also proposed for functions such as to sense bitter compounds and succinate that will guide hyperplasia of tuft cells [ 6 , 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Interleukin-4 Promotes Tuft Cell Differentiation and Acetylcholine Production in Intestinal Organoids of Non-Human Primate

Inaba

Arinaga

Tanaka

et al. 2021

IJMS

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In the intestine, the innate immune system excludes harmful substances and invading microorganisms. Tuft cells are taste-like chemosensory cells found in the intestinal epithelium involved in the activation of group 2 innate lymphoid cells (ILC2). Although tuft cells in other tissues secrete the neurotransmitter acetylcholine (ACh), their function in the gut remains poorly understood. In this study, we investigated changes in the expression of genes and cell differentiation of the intestinal epithelium by stimulation with interleukin-4 (IL-4) or IL-13 in macaque intestinal organoids. Transcriptome analysis showed that tuft cell marker genes were highly expressed in the IL-4- and IL-13-treated groups compared with the control, and the gene expression of choline acetyltransferase (ChAT), a synthesis enzyme of ACh, was upregulated in IL-4- and IL-13-treated groups. ACh accumulation was observed in IL-4-induced organoids using high-performance liquid chromatography-mass spectrometry (HPLC/MS), and ACh strongly released granules from Paneth cells. This study is the first to demonstrate ACh upregulation by IL-4 induction in primates, suggesting that IL-4 plays a role in Paneth cell granule secretion via paracrine stimulation.

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“…Four clusters showed strong expression of EPCAM and, based on expression of previously reported marker genes (9,31,32), were putatively identified as parietal, mucous, tuft and enterochromaffinlike (ECL) cells (Figure 3C and Supplementary Table 6). The tuft cell cluster represented 1.1% of the total cells and 3.6% of epithelial cells (Supplementary Table 7), and showed enriched expression of canonical tuft cell genes POU2F3, GFI1b, TRPM5 and IL-25 receptor IL17RB (Figure 4A).…”

Section: A Cell Atlas For the Ovine Abomasal Mucosamentioning

confidence: 89%

“…Increased goblet cell mucus production and gut contractility result in helminth expulsion from the GI tract, referred to as the "weep and sweep" response (8). In mice, tuft cells are proposed to act as sentinels of GI mucosal immunity, sensing the presence of parasites and triggering the type 2 response (4)(5)(6)(9)(10)(11). While the tuft cell-ILC2 axis was identified in murine SI, nothing is known of tuft cells in immunity in other host species and in other regions of the GI tract.…”

Section: Introductionmentioning

confidence: 99%

Tuft Cells Increase Following Ovine Intestinal Parasite Infections and Define Evolutionarily Conserved and Divergent Responses

et al. 2021

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Helminth parasite infections of humans and livestock are a global health and economic problem. Resistance of helminths to current drug treatment is an increasing problem and alternative control approaches, including vaccines, are needed. Effective vaccine design requires knowledge of host immune mechanisms and how these are stimulated. Mouse models of helminth infection indicate that tuft cells, an unusual type of epithelial cell, may ‘sense’ infection in the small intestine and trigger a type 2 immune response. Currently nothing is known of tuft cells in immunity in other host species and in other compartments of the gastrointestinal (GI) tract. Here we address this gap and use immunohistochemistry and single cell RNA-sequencing to detail the presence and gene expression profile of tuft cells in sheep following nematode infections. We identify and characterize tuft cells in the ovine abomasum (true stomach of ruminants) and show that they increase significantly in number following infection with the globally important nematodes Teladorsagia circumcincta and Haemonchus contortus. Ovine abomasal tuft cells show enriched expression of tuft cell markers POU2F3, GFI1B, TRPM5 and genes involved in signaling and inflammatory pathways. However succinate receptor SUCNR1 and free fatty acid receptor FFAR3, proposed as ‘sensing’ receptors in murine tuft cells, are not expressed, and instead ovine tuft cells are enriched for taste receptor TAS2R16 and mechanosensory receptor ADGRG6. We also identify tuft cell sub-clusters at potentially different stages of maturation, suggesting a dynamic process not apparent from mouse models of infection. Our findings reveal a tuft cell response to economically important parasite infections and show that while tuft cell effector functions have been retained during mammalian evolution, receptor specificity has diverged. Our data advance knowledge of host-parasite interactions in the GI mucosa and identify receptors that may potentiate type 2 immunity for optimized control of parasitic nematodes.

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Tuning tuft cells: new ligands and effector functions reveal tissue-specific function

Cited by 47 publications

References 58 publications

Intestinal epithelial tuft cell induction is negated by a murine helminth and its secreted products

Intestinal epithelial tuft cell induction is negated by a murine helminth and its secreted products

Interleukin-4 Promotes Tuft Cell Differentiation and Acetylcholine Production in Intestinal Organoids of Non-Human Primate

Tuft Cells Increase Following Ovine Intestinal Parasite Infections and Define Evolutionarily Conserved and Divergent Responses

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