Journal Article

Tuft-cell-derived IL-25 regulates an intestinal ILC2–epithelial response circuit

von Moltke, Jakob, Ji, Ming, Liang, Hong-Erh, Locksley, Richard M.

2016

Overview

Epithelial tuft cells are shown to be the source of intestinal interleukin (IL)-25 that is required for activation of type 2 innate lymphoid cells (ILC2s), ILC2-regulated tuft and goblet cell expansion, and control of parasite infection. Epithelial tuft cells in type 2 immunity The 'weep-and-sweep' response to parasitic helminths and allergens, in which parasites are ejected by increased propulsive activity of the gut combined with fluid and mucus secretion, is a manifestation of type 2 (or allergic) immunity involving the activation of group 2 innate lymphoid cells (ILC2s). The epithelium in the small intestine consists of five or more distinct cellular lineages, including tuft cells, whose functions remain unclear. Two papers in this issue of Nature demonstrate a role for tuft cells in the response to parasites. Richard Locksley and colleagues show that tuft cells are the source of the interleukin 25 (IL-25) that is required for activation of ILC2s, ILC2-regulated tuft and goblet cell expansion, and control of parasite infection. Philippe Jay and colleagues show that tuft cells secrete IL-25 via an IL-13/IL-4R -dependent feedback loop. Parasitic helminths and allergens induce a type 2 immune response leading to profound changes in tissue physiology, including hyperplasia of mucus-secreting goblet cells 1 and smooth muscle hypercontractility 2 . 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 (T H 2 cells) 3 . 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 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 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 12 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/127/1213 / 631/250/2504/2506 / 631/250/255/1715 / 631/250/347 / 631/532/2437 / Animals / Antigens, Helminth - immunology / Cell Proliferation / Cytokines / Epithelial cells / Female / Goblet Cells - cytology / Goblet Cells - immunology / Homeostasis / Humanities and Social Sciences / Immune response / Immunity / Immunity, Innate - immunology / Immunity, Mucosal - immunology / Immunology / Infections / Interleukin-13 - immunology / Interleukin-17 - immunology / Interleukin-17 - metabolism / Interleukins / Intestinal Mucosa - cytology / Intestinal Mucosa - immunology / Intestinal Mucosa - metabolism / Intestine, Small - cytology / Intestine, Small - immunology / Intestines / letter / Lymphocytes - cytology / Lymphocytes - immunology / Male / Mice / multidisciplinary / Nippostrongylus - immunology / Parasites / Physiological aspects / Physiological research / Rodents / Science / Signal Transduction / Small intestine / Smooth muscle / Stem Cells - cytology / Stem Cells - immunology / Strongylida Infections - immunology / Th2 Cells - cytology / Th2 Cells - immunology / Worms