c-FLIP is crucial for IL-7/IL-15-dependent NKp46 + ILC development and protection from intestinal inflammation in mice

Nat Commun. 2020 Feb 26;11(1):1056. doi: 10.1038/s41467-020-14782-3.

Abstract

NKp46+ innate lymphoid cells (ILC) modulate tissue homeostasis and anti-microbial immune responses. ILC development and function are regulated by cytokines such as Interleukin (IL)-7 and IL-15. However, the ILC-intrinsic pathways translating cytokine signals into developmental programs are largely unknown. Here we show that the anti-apoptotic molecule cellular FLICE-like inhibitory protein (c-FLIP) is crucial for the generation of IL-7/IL-15-dependent NKp46+ ILC1, including conventional natural killer (cNK) cells, and ILC3. Cytokine-induced phosphorylation of signal transducer and activator of transcription 5 (STAT5) precedes up-regulation of c-FLIP, which protects developing NKp46+ ILC from TNF-induced apoptosis. NKp46+ ILC-specific inactivation of c-FLIP leads to the loss of all IL-7/IL-15-dependent NKp46+ ILC, thereby inducing early-onset chronic colitis and subsequently microbial dysbiosis; meanwhile, the depletion of cNK, but not NKp46+ ILC1/3, aggravates experimental colitis. In summary, our data demonstrate a non-redundant function of c-FLIP for the generation of NKp46+ ILC, which protect T/B lymphocyte-sufficient mice from intestinal inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / genetics
  • Antigens, Ly / metabolism*
  • Apoptosis / physiology
  • B-Lymphocytes / immunology
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
  • Cells, Cultured
  • Colitis / chemically induced
  • Colitis / pathology
  • Colitis / prevention & control*
  • Interleukin-15 / metabolism*
  • Interleukin-7 / metabolism*
  • Killer Cells, Natural / immunology
  • Mice
  • Mice, Knockout
  • Natural Cytotoxicity Triggering Receptor 1 / genetics
  • Natural Cytotoxicity Triggering Receptor 1 / metabolism*
  • Phosphorylation
  • STAT5 Transcription Factor / metabolism*
  • T-Lymphocytes / immunology

Substances

  • Antigens, Ly
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Cflar protein, mouse
  • Interleukin-15
  • Interleukin-7
  • Natural Cytotoxicity Triggering Receptor 1
  • Ncr1 protein, mouse
  • STAT5 Transcription Factor
  • Stat5a protein, mouse
  • interleukin-7, mouse