期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 216, 期 9, 页码 2010-2023出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20182164
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资金
- Research Foundation Flanders
- Bijzonder Onderzoeksfonds grant from the University of Ghent
- European Research Council (ERC) Advanced Grant
- ERC Consolidator Grant
- ERC Excellence of Science grant [G0G7318N]
- ERC under H2020 European Research Council (Targeting Innate Lymphoid Cells) [694502]
- Agence Nationale de la Recherche
- Equipe Labellisee La Ligue, Ligue Contre le Cancer
- MSD-Avenir
- Innate Pharma
- Methusalem grant [BOF16/MET_V/007]
The ubiquitin-editing enzyme A20 is a well-known regulator of immune cell function and homeostasis. In addition, A20 protects cells from death in an ill-defined manner. While most studies focus on its role in the TNF-receptor complex, we here identify a novel component in the A20-mediated decision between life and death. Loss of A20 in NK cells led to spontaneous NK cell death and severe NK cell lymphopenia. The few remaining NK cells showed an immature, hyperactivated phenotype, hallmarked by the basal release of cytokines and cytotoxic molecules. NK-A20(-/-) cells were hypersensitive to TNF-induced cell death and could be rescued, at least partially, by a combined deficiency with TNF. Unexpectedly, rapamycin, a well-established inhibitor of mTOR, also strongly protected NK-A20(-/-) cells from death, and further studies revealed that A20 restricts mTOR activation in NK cells. This study therefore maps A20 as a crucial regulator of mTOR signaling and underscores the need for a tightly balanced mTOR pathway in NK cell homeostasis.
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