TSLP links intestinal nutrient sensing with amplification of the ILC2-tuft cell circuit

  • Nat Immunol. 2025 Dec;26(12):2218-2226. doi: 10.1038/s41590-025-02328-y.
Chang Liao  1 ,  Elvira Mennillo  1 ,  Michael G Kattah  1 ,  Ming Ji  2 ,  Zhi-En Wang  2 ,  Daniel J Drucker  3 ,  Hong-Erh Liang  1 ,  Richard M Locksley  4  5
Affiliations
  • 1. Department of Medicine, University of California, San Francisco, CA, USA.
  • 2. Howard Hughes Medical Institute, University of California, San Francisco, CA, USA.
  • 3. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
  • 4. Department of Medicine, University of California, San Francisco, CA, USA. [email protected].
  • 5. Howard Hughes Medical Institute, University of California, San Francisco, CA, USA. [email protected].
PMID: 41225178 DOI: 10.1038/s41590-025-02328-y
Abstract

Group 2 innate lymphocytes (ILC2s) are prevalent in small intestine but their role during homeostasis is unclear. Here we show that thymic stromal lymphopoietin (TSLP)-a cytokine implicated in ILC2 activation-is expressed constitutively in subepithelial fibroblasts, including telocytes and crypt-associated trophocytes, which are specialized fibroblasts necessary to sustain epithelial identity. Feeding increases TSLP and induces ILC2 type 2 cytokines that are attenuated by deletion of TSLP in fibroblasts or TSLP receptor on ILC2s. Both mouse and human intestinal fibroblasts express receptors for glucagon-like peptide-2 (GLP-2)-an intestinotrophic growth factor released by enteroendocrine cells following food intake. GLP-2 promotes intestinal TSLP in mouse and human intestinal fibroblasts, and TSLP-dependent ILC2 activation and tuft cell hyperplasia in mice, thus linking nutrient detection with ILC2-mediated amplification of the tuft cell chemosensory circuit that promotes epithelial surveillance of ingested cargo.

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