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c-FLIP is crucial for IL-7/IL-15-dependent NKp46 ILC development and protection from intestinal inflammation in mice.
Bank, Ute Deiser, Katrin Plaza-Sirvent, Carlos Osbelt, Lisa Witte, Amelie Knop, Laura Labrenz, Rebecca Jänsch, Robert Richter, Felix Biswas, Aindrila
Bank, Ute
Deiser, Katrin
Plaza-Sirvent, Carlos
Osbelt, Lisa
Witte, Amelie
Knop, Laura
Labrenz, Rebecca
Jänsch, Robert
Richter, Felix
Biswas, Aindrila
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2020-02-26
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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.
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Nat Commun. 2020 Feb 26;11(1):1056. doi: 10.1038/s41467-020-14782-3.
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en
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2041-1723
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Attribution-NonCommercial-ShareAlike 4.0 International