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

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 and Thomas Schüler ()
Additional contact information
Ute Bank: Otto-von-Guericke University
Katrin Deiser: Otto-von-Guericke University
Carlos Plaza-Sirvent: Otto-von-Guericke University
Lisa Osbelt: Otto-von-Guericke University
Amelie Witte: Otto-von-Guericke University
Laura Knop: Otto-von-Guericke University
Rebecca Labrenz: Otto-von-Guericke University
Robert Jänsch: Otto-von-Guericke University
Felix Richter: Otto-von-Guericke University
Aindrila Biswas: Otto-von-Guericke University
Ana C. Zenclussen: Otto-von-Guericke University
Eric Vivier: CNRS
Chiara Romagnani: Leibniz Association
Anja A. Kühl: iPATH
Ildiko R. Dunay: Otto-von-Guericke University
Till Strowig: Helmholtz Centre for Infection Research
Ingo Schmitz: Otto-von-Guericke University
Thomas Schüler: Otto-von-Guericke University

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14782-3

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