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

By Jakob von Moltke, M. Ji, Hong-Erh Liang, R. Locksley. Nature, 2015

1,087 citations recorded by the source corpus.

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.

Subfields: Immunology, Surgery

View Paper: https://www.semanticscholar.org/paper/73503afb9c3bad98a2a2527fc85271d0dc548097

How researchers see this paper

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In Immunology

1. S. Gaffen
2. D. Cua
3. M. McGeachy
4. O. Harrison
5. Y. Belkaid
6. R. Flavell
7. Ming O. Li
8. C. Tato

In Surgery

1. Y. Belkaid
2. O. Harrison

Citations in the corpus

• Homeostatic immunity and the microbiota (2017, positive): “Tuft cells, which are tastechemosensory epithelial cells, accumulate during colonization with a commensal protozoan or a nematode and represent the primary source of interleukin-25 post colonization, which indirectly induces tuft cell expansion (Howitt et al., 2016; von Moltke et al., 2016).”
• The IL-17 family of cytokines in health and disease (2019, background): “IL-25 is produced constitutively by intestinal tuft cells, a population of epithelial chemosensory cells capable of detecting harmful environmental agents (von Moltke et al., 2016).”