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

Published in: Nature Communications, 2020, 11 (1), pp.1056. ⟨10.1038/s41467-020-14782-3⟩

Authors: Ute Bank, Katrin Deiser, Carlos Plaza-Sirvent, Lisa Osbelt, Amelie Witte, Laura Knop, Rebecca Labrenz, Robert Jänsch, Felix Richter, Aindrila Biswas, Ana C Zenclussen, Eric Vivier, Chiara Romagnani, Anja A Kühl, Ildiko R Dunay, Till Strowig, Ingo Schmitz, Thomas Schüler

Summary

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.

Link to HAL – inserm-02506954

Link to DOI – 10.1038/s41467-020-14782-3