Gut Bacteria Induce Granzyme B Expression in Human Colonic ILC3s In Vitro in an IL-15-Dependent Manner

J Immunol. 2021 Jun 15;206(12):3043-3052. doi: 10.4049/jimmunol.2000239. Epub 2021 Jun 11.


Group 3 innate lymphoid cells (ILC3s) in the gut mucosa have long been thought to be noncytotoxic lymphocytes that are critical for homeostasis of intestinal epithelial cells through secretion of IL-22. Recent work using human tonsillar cells demonstrated that ILC3s exposed to exogenous inflammatory cytokines for a long period of time acquired expression of granzyme B, suggesting that under pathological conditions ILC3s may become cytotoxic. We hypothesized that inflammation associated with bacterial exposure might trigger granzyme B expression in gut ILC3s. To test this, we exposed human colon lamina propria mononuclear cells to a panel of enteric bacteria. We found that the Gram-negative commensal and pathogenic bacteria induced granzyme B expression in a subset of ILC3s that were distinct from IL-22-producing ILC3s. A fraction of granzyme B+ ILC3s coexpressed the cytolytic protein perforin. Granzyme B expression was mediated, in part, by IL-15 produced upon exposure to bacteria. ILC3s coexpressing all three IL-15R subunits (IL15Rα/β/γ) increased following bacterial stimulation, potentially allowing for cis presentation of IL-15 during bacterial exposure. Additionally, a large frequency of colonic myeloid dendritic cells expressed IL-15Rα, implicating myeloid dendritic cells in trans presentation of IL-15 to ILC3s. Tonsillar ILC3s minimally expressed granzyme B when exposed to the same bacteria or to rIL-15. Overall, these data establish the novel, to our knowledge, finding that human colonic ILC3s can express granzyme B in response to a subset of enteric bacteria through a process mediated by IL-15. These observations raise new questions about the multifunctional role of human gut ILC3s.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acinetobacter / immunology*
  • Colon / immunology
  • Gastrointestinal Microbiome / immunology
  • Granzymes / immunology*
  • Humans
  • Immunity, Innate / immunology
  • Interleukin-15 / immunology*
  • Lymphocytes / immunology*
  • Ruminococcus / immunology*
  • Salmonella typhimurium / immunology*


  • IL15 protein, human
  • Interleukin-15
  • GZMB protein, human
  • Granzymes

Supplementary concepts

  • Acinetobacter junii
  • Ruminococcus bromii