title: Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit.
abstract: Parasitic helminths and allergens induce a type 2 immune response leading to profound changes in tissue physiology, including hyperplasia of mucus-secreting goblet cells and smooth muscle hypercontractility. This response, known as 'weep and sweep', requires interleukin (IL)-13 production by tissue-resident group 2 innate lymphoid cells (ILC2s) and recruited type 2 helper T cells (TH2 cells). Experiments in mice and humans have demonstrated requirements for the epithelial cytokines IL-33, thymic stromal lymphopoietin (TSLP) and IL-25 in the activation of ILC2s, but the sources and regulation of these signals remain poorly defined. In the small intestine, the epithelium consists of at least five distinct cellular lineages, including the tuft cell, whose function is unclear. Here we show that tuft cells constitutively express IL-25 to sustain ILC2 homeostasis in the resting lamina propria in mice. After helminth infection, tuft-cell-derived IL-25 further activates ILC2s to secrete IL-13, which acts on epithelial crypt progenitors to promote differentiation of tuft and goblet cells, leading to increased frequencies of both. Tuft cells, ILC2s and epithelial progenitors therefore comprise a response circuit that mediates epithelial remodelling associated with type 2 immunity in the small intestine, and perhaps at other mucosal barriers populated by these cells.
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California 94143-0795, USA.
authors.forename: Jakob
authors.initials: J
authors.lastname: von Moltke
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California 94143-0795, USA.|Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94143-0795, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Ji
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California 94143-0795, USA.
authors.forename: Hong-Erh
authors.initials: HE
authors.lastname: Liang
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California 94143-0795, USA.|Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94143-0795, USA.|Department of Microbiology &Immunology, University of California San Francisco, San Francisco, California 94143-0795, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Locksley
mesh_terms: D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology; D049109:Cell Proliferation; D005260:Female; D020397:Goblet Cells / Q000166:cytology / Q000276:immunology; D006706:Homeostasis; D007113:Immunity, Innate / 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; D007421:Intestine, Small / Q000166:cytology / Q000276:immunology; D008214:Lymphocytes / Q000166:cytology* / Q000276:immunology*; D008297:Male; D051379:Mice; D009559:Nippostrongylus / Q000276:immunology; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000276:immunology; D017206:Strongylida Infections / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology
chemical_list: D000947:Antigens, Helminth; D018793:Interleukin-13; D020381:Interleukin-17