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Regulation of immune responses by tuft cells

Nature Reviews Immunology volume 19, pages 584–593 (2019)Cite this article

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Abstract

Tuft cells are rare, secretory epithelial cells that generated scant immunological interest until contemporaneous reports in 2016 linked tuft cells with type 2 immunity in the small intestine. Tuft cells have the capacity to produce an unusual spectrum of biological effector molecules, including IL-25, eicosanoids implicated in allergy (such as cysteinyl leukotrienes and prostaglandin D2) and the neurotransmitter acetylcholine. In most cases, the extracellular signals controlling tuft cell effector function are unknown, but signal transduction is thought to proceed via canonical, G protein-coupled receptor-dependent pathways involving components of the signalling pathway used by type II taste bud cells to sense sweet, bitter and umami compounds. Tuft cells are ideally positioned as chemosensory sentinels that can detect and relay information from diverse luminal substances via what appear to be stereotyped outputs to initiate both positive and aversive responses through populations of immune and neuronal cells. Despite recent insights, numerous questions remain regarding tuft cell lineage, diversity and effector mechanisms and how tuft cells interface with the immunological niche in the tissues where they reside.

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Fig. 1: The small intestinal tuft cell–ILC2 circuit.
Fig. 2: GPCR signalling in tuft cells and tuft-like cells.
Fig. 3: Biosynthetic pathways for putative tuft cell effector molecules.

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Acknowledgements

The authors are grateful for comments from laboratory members. This work was supported by funds from the US National Institutes of Health, the Howard Hughes Medical Institute, the Strategic Asthma Basic Research Center at the University of California–San Francisco (UCSF) and the Australian National Health and Medical Research Council to R.M.L. C.S. is supported by fellowships from the Swiss National Science Foundation. C.E.O. is supported by the Gastroenterology T32 Training Grant at UCSF.

Competing interests

The authors declare no competing interests.

Reviewer information

Nature Reviews Immunology thanks N. Cohen and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Medicine, University of California–San Francisco, San Francisco, CA, USA

    Christoph Schneider, Claire E. O’Leary & Richard M. Locksley

  2. Department of Microbiology & Immunology, University of California–San Francisco, San Francisco, CA, USA

    Richard M. Locksley

  3. Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA

    Richard M. Locksley

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  1. Christoph Schneider
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Glossary

Transient receptor potential cation channel

Calcium-gated, inwardly rectifying cation channel that mediates membrane depolarization downstream of canonical taste receptors and other G protein-coupled receptors involved in tuft cell activation.

Group 2 innate lymphoid cells

(ILC2s). Innate immune cells producing IL-5 and IL-13 with early roles in type 2 immune responses.

Hassall’s corpuscles

Cornified bodies of epithelial cells in the thymic medulla, which were previously described to be a site of thymic stromal lymphopoietin (TSLP) expression and important for the instruction of dendritic cells to induce regulatory T cell differentiation.

G protein-coupled receptor

(GPCR). GPCRs are a large group of receptors that can bind to a diverse set of molecules (such as metabolites, chemokines, hormones and neurotransmitters) and can induce intracellular signalling by coupling to heterotrimeric GTP-regulated signalling proteins.

Krebs cycle

Also known as the tricarboxylic acid cycle and citric acid cycle. This cycle is a series of enzymatic reactions used in aerobic metabolism to release energy through the oxidation of acetyl-CoA to yield ATP and carbon dioxide.

Umami tastants

Also known as savoury taste. One of the five basic tastes. Umami stimuli, such as the prototypical example monosodium glutamate, are sensed by multiple taste receptors expressed by type II taste cells.

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Schneider, C., O’Leary, C.E. & Locksley, R.M. Regulation of immune responses by tuft cells. Nat Rev Immunol 19, 584–593 (2019). https://doi.org/10.1038/s41577-019-0176-x

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