Tuft Cells—Systemically Dispersed Sensory Epithelia Integrating Immune and Neural Circuitry

Tuft cells—rare solitary chemosensory cells in mucosal epithelia—are undergoing intense scientific scrutiny fueled by recent discovery of unsuspected connections to type 2 immunity. These cells constitute a conduit by which ligands from the external space are sensed via taste-like signaling pathways to generate outputs unique among epithelial cells: the cytokine IL-25, eicosanoids associated with allergic immunity, and the neurotransmitter acetylcholine. The classic type II taste cell transcription factor POU2F3 is lineage defining, suggesting a conceptualization of these cells as widely distributed environmental sensors with effector functions interfacing type 2 immunity and neural circuits. Increasingly refined single-cell analytics have revealed diversity among tuft cells that extends from nasal epithelia and type II taste cells to ex- Aire-expressing medullary thymic cells and small-intestine cells that mediate tissue remodeling in response to colonizing helminths and protists.

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Faculty Opinions recommendation of Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726123106.793523446 ◽

2016 ◽

Author(s):

Jonathan Kaunitz

Keyword(s):

Type 2 Immunity ◽

Tuft Cells

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Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 immunity in the mouse small intestine

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1720758115 ◽

2018 ◽

Vol 115 (21) ◽

pp. 5552-5557 ◽

Cited By ~ 61

Author(s):

Weiwei Lei ◽

Wenwen Ren ◽

Makoto Ohmoto ◽

Joseph F. Urban ◽

Ichiro Matsumoto ◽

...

Keyword(s):

Goblet Cell ◽

Mucosal Immunity ◽

Cell Activation ◽

Nippostrongylus Brasiliensis ◽

Infectious Agents ◽

Cell Hyperplasia ◽

Type 2 Immunity ◽

Tuft Cell ◽

Tuft Cells

The hallmark features of type 2 mucosal immunity include intestinal tuft and goblet cell expansion initiated by tuft cell activation. How infectious agents that induce type 2 mucosal immunity are detected by tuft cells is unknown. Published microarray analysis suggested that succinate receptor 1 (Sucnr1) is specifically expressed in tuft cells. Thus, we hypothesized that the succinate–Sucnr1 axis may be utilized by tuft cells to detect certain infectious agents. Here we confirmed that Sucnr1 is specifically expressed in intestinal tuft cells but not in other types of intestinal epithelial cells, and demonstrated that dietary succinate induces tuft and goblet cell hyperplasia via Sucnr1 and the tuft cell-expressed chemosensory signaling elements gustducin and Trpm5. Conventional mice with a genetic Sucnr1 deficiency (Sucnr1−/−) showed diminished immune responses to treatment with polyethylene glycol and streptomycin, which are known to enhance microbiota-derived succinate, but responded normally to inoculation with the parasitic worm Nippostrongylus brasiliensis that also produces succinate. Thus, Sucnr1 is required for microbiota-induced but not for a generalized worm-induced type 2 immunity.

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Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit

10.1101/310110 ◽

2018 ◽

Author(s):

Marija S. Nadjsombati ◽

John W. McGinty ◽

Miranda R. Lyons-Cohen ◽

Joshua L. Pollack ◽

G.A. Nagana Gowda ◽

...

Keyword(s):

Small Intestine ◽

Immune Responses ◽

Innate Immune ◽

Nippostrongylus Brasiliensis ◽

Transduction Pathway ◽

Type 2 Immunity ◽

Tuft Cell ◽

Tuft Cells ◽

Taste Transduction

SummaryInitiation of immune responses requires innate immune sensing, but immune detection of the helminths, protists, and allergens that stimulate type 2 immunity remains poorly understood. In the small intestine, type 2 immune responses are regulated by a tuft cell-ILC2 signaling circuit. Tuft cells express components of a canonical taste transduction pathway, including the membrane channel TRPM5, but the ligands and receptors that activate tuft cells in the small intestine are unknown. Here we identify succinate as the first ligand that activates intestinal tuft cells to initiate type 2 immune responses. Using mRNA-Seq on tuft cells from different tissues, we show that all tuft cells express the intracellular taste transduction pathway, but expression of upstream receptors is tissue-specific. In the small intestine, tuft cells express the succinate receptor SUCNR1. Remarkably, providing succinate in drinking water is sufficient to induce a multifaceted type 2 immune response in the murine small intestine, involving all known components of the tuft-ILC2 circuit. The helminthNippostrongylus brasiliensissecretes succinate as a metabolite, and sensing of both succinate andN. brasiliensisrequires tuft cells and TRPM5, suggesting a novel paradigm in which type 2 immunity monitors microbial metabolism. Manipulation of succinate sensing may have therapeutic benefit in numerous intestinal diseases.

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