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Immunity. 2018 Jul 17;49(1):33-41.e7. doi: 10.1016/j.immuni.2018.06.016.

Detection of Succinate by Intestinal Tuft Cells Triggers a Type 2 Innate Immune Circuit.

Author information

1
Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA.
2
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
3
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
4
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
5
Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA.
6
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
7
Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA. Electronic address: jmoltke@uw.edu.

Abstract

In the small intestine, type 2 responses are regulated by a signaling circuit that involves tuft cells and group 2 innate lymphoid cells (ILC2s). Here, we identified the microbial metabolite succinate as an activating ligand for small intestinal (SI) tuft cells. Sequencing analyses of tuft cells isolated from the small intestine, gall bladder, colon, thymus, and trachea revealed that expression of tuft cell chemosensory receptors is tissue specific. SI tuft cells expressed the succinate receptor (SUCNR1), and providing succinate in drinking water was sufficient to induce a multifaceted type 2 immune response via the tuft-ILC2 circuit. The helminth Nippostrongylus brasiliensis and a tritrichomonad protist both secreted succinate as a metabolite. In vivo sensing of the tritrichomonad required SUCNR1, whereas N. brasiliensis was SUCNR1 independent. These findings define a paradigm wherein tuft cells monitor microbial metabolites to initiate type 2 immunity and suggest the existence of other sensing pathways triggering the response to helminths.

KEYWORDS:

ILC2; chemosensing; helminth; nippostrongylus brasiliensis; protist; small intestine; succinate; tritrichomonas; tuft cell; type 2 immunity

PMID:
30021144
PMCID:
PMC6084797
DOI:
10.1016/j.immuni.2018.06.016
[Indexed for MEDLINE]
Free PMC Article

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