Group 3 innate lymphoid cells produce the growth factor HB-EGF to protect the intestine from TNF-mediated inflammation

Nat Immunol. 2022 Feb;23(2):251-261. doi: 10.1038/s41590-021-01110-0. Epub 2022 Jan 31.


Tumor necrosis factor (TNF) drives chronic inflammation and cell death in the intestine, and blocking TNF is a therapeutic approach in inflammatory bowel disease (IBD). Despite this knowledge, the pathways that protect the intestine from TNF are incompletely understood. Here we demonstrate that group 3 innate lymphoid cells (ILC3s) protect the intestinal epithelium from TNF-induced cell death. This occurs independent of interleukin-22 (IL-22), and we identify that ILC3s are a dominant source of heparin-binding epidermal growth factor-like growth factor (HB-EGF). ILC3s produce HB-EGF in response to prostaglandin E2 (PGE2) and engagement of the EP2 receptor. Mice lacking ILC3-derived HB-EGF exhibit increased susceptibility to TNF-mediated epithelial cell death and experimental intestinal inflammation. Finally, human ILC3s produce HB-EGF and are reduced from the inflamed intestine. These results define an essential role for ILC3-derived HB-EGF in protecting the intestine from TNF and indicate that disruption of this pathway contributes to IBD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Epithelial Cells / immunology
  • Heparin-binding EGF-like Growth Factor / immunology*
  • Immunity, Innate / immunology*
  • Inflammation / immunology*
  • Intestinal Mucosa / immunology
  • Intestines / immunology*
  • Lymphocytes / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Signal Transduction / immunology
  • Tumor Necrosis Factor-alpha / immunology*


  • Hbegf protein, mouse
  • Heparin-binding EGF-like Growth Factor
  • Tumor Necrosis Factor-alpha