title: Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites.
abstract: Helminth parasitic infections are a major global health and social burden. The host defence against helminths such as Nippostrongylus brasiliensis is orchestrated by type 2 cell-mediated immunity. Induction of type 2 cytokines, including interleukins (IL) IL-4 and IL-13, induce goblet cell hyperplasia with mucus production, ultimately resulting in worm expulsion. However, the mechanisms underlying the initiation of type 2 responses remain incompletely understood. Here we show that tuft cells, a rare epithelial cell type in the steady-state intestinal epithelium, are responsible for initiating type 2 responses to parasites by a cytokine-mediated cellular relay. Tuft cells have a Th2-related gene expression signature and we demonstrate that they undergo a rapid and extensive IL-4Rα-dependent amplification following infection with helminth parasites, owing to direct differentiation of epithelial crypt progenitor cells. We find that the Pou2f3 gene is essential for tuft cell specification. Pou2f3(-/-) mice lack intestinal tuft cells and have defective mucosal type 2 responses to helminth infection; goblet cell hyperplasia is abrogated and worm expulsion is compromised. Notably, IL-4Rα signalling is sufficient to induce expansion of the tuft cell lineage, and ectopic stimulation of this signalling cascade obviates the need for tuft cells in the epithelial cell remodelling of the intestine. Moreover, tuft cells secrete IL-25, thereby regulating type 2 immune responses. Our data reveal a novel function of intestinal epithelial tuft cells and demonstrate a cellular relay required for initiating mucosal type 2 immunity to helminth infection.
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34094 Montpellier, France.|INSERM, U1191, F-34094 Montpellier, France.|Université de Montpellier, F-34000 Montpellier, France.
authors.forename: François
authors.initials: F
authors.lastname: Gerbe
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34094 Montpellier, France.|INSERM, U1191, F-34094 Montpellier, France.|Université de Montpellier, F-34000 Montpellier, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Sidot
authors.affiliation: Institute of Immunology and Infection Research, School of Biological Sciences and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3JT, UK.
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: Smyth
authors.affiliation: Monell Chemical Senses Center, 3500 Market Street, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ohmoto
authors.affiliation: Monell Chemical Senses Center, 3500 Market Street, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Matsumoto
authors.affiliation: Université de Montpellier, F-34000 Montpellier, France.|Institut de Génétique Moléculaire de Montpellier, CNRS, UMR5535, F-34293 Montpellier, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Dardalhon
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34094 Montpellier, France.|INSERM, U1191, F-34094 Montpellier, France.|Université de Montpellier, F-34000 Montpellier, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cesses
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34094 Montpellier, France.|INSERM, U1191, F-34094 Montpellier, France.|Université de Montpellier, F-34000 Montpellier, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Garnier
authors.affiliation: Université de Montpellier, F-34000 Montpellier, France.|Institut de Génétique Moléculaire de Montpellier, CNRS, UMR5535, F-34293 Montpellier, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Pouzolles
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34094 Montpellier, France.|INSERM, U1191, F-34094 Montpellier, France.|Université de Montpellier, F-34000 Montpellier, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Brulin
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34094 Montpellier, France.|INSERM, U1191, F-34094 Montpellier, France.|Université de Montpellier, F-34000 Montpellier, France.
authors.forename: Marco
authors.initials: M
authors.lastname: Bruschi
authors.affiliation: Institute of Immunology and Infection Research, School of Biological Sciences and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3JT, UK.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Harcus
authors.affiliation: Université de Montpellier, F-34000 Montpellier, France.|Institut de Génétique Moléculaire de Montpellier, CNRS, UMR5535, F-34293 Montpellier, France.
authors.forename: Valérie S
authors.initials: VS
authors.lastname: Zimmermann
authors.affiliation: Université de Montpellier, F-34000 Montpellier, France.|Institut de Génétique Moléculaire de Montpellier, CNRS, UMR5535, F-34293 Montpellier, France.
authors.forename: Naomi
authors.initials: N
authors.lastname: Taylor
authors.affiliation: Institute of Immunology and Infection Research, School of Biological Sciences and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3JT, UK.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Maizels
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34094 Montpellier, France.|INSERM, U1191, F-34094 Montpellier, France.|Université de Montpellier, F-34000 Montpellier, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Jay
mesh_terms: D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation; D025461:Feedback, Physiological; D005260:Female; D020397:Goblet Cells / Q000166:cytology / Q000276:immunology; D018928:Immunity, Mucosal / Q000276:immunology*; D018793:Interleukin-13 / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D009559:Nippostrongylus / Q000276:immunology*; D050810:Octamer Transcription Factors / Q000172:deficiency; D010271:Parasites / Q000276:immunology*; D019948:Receptors, Interleukin-4 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013234:Stem Cells / Q000166:cytology / Q000276:immunology; D017206:Strongylida Infections / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology
chemical_list: D018793:Interleukin-13; D020381:Interleukin-17; D050810:Octamer Transcription Factors; C084342:Pou2f3 protein, mouse; D019948:Receptors, Interleukin-4