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

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

Author information

1
Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
2
Systems-Oriented Immunology and Inflammation Research Group, Department of Immune Control, Helmholtz Centre for Infection Research, Braunschweig, Germany.
3
Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
4
Microbial Immune Regulation Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
5
Institute of Inflammation and Neurodegeneration, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
6
Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
7
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France.
8
Service d'Immunologie, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France.
9
Innate Pharma Research Labs., Innate Pharma, Marseille, France.
10
Innate Immunity, German Rheumatism Research Center (DRFZ), Leibniz Association, Berlin, Germany.
11
Medical Department I, Charité - University Medical Center Berlin, Berlin, Germany.
12
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, iPATH, Berlin, Germany.
13
Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany. thomas.schueler@med.ovgu.de.

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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