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J Exp Med. 2017 Feb;214(2):491-510. doi: 10.1084/jem.20160869. Epub 2017 Jan 5.

Cell cycle progression dictates the requirement for BCL2 in natural killer cell survival.

Author information

1
Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), 13288 Marseille, France.
2
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
3
Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
4
School of Medicine, Tsinghua University, Beijing 100084, China.
5
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
6
Service Immunologie, Hôpital de la Conception, Assistance Publique Hôpitaux de Marseille (APHM), 13288 Marseille, France.
7
Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), 13288 Marseille, France ugolini@ciml.univ-mrs.fr huntington@wehi.edu.au.
8
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia ugolini@ciml.univ-mrs.fr huntington@wehi.edu.au.

Abstract

Natural killer (NK) cells are innate lymphoid cells with antitumor functions. Using an N-ethyl-N-nitrosourea (ENU)-induced mutagenesis screen in mice, we identified a strain with an NK cell deficiency caused by a hypomorphic mutation in the Bcl2 (B cell lymphoma 2) gene. Analysis of these mice and the conditional deletion of Bcl2 in NK cells revealed a nonredundant intrinsic requirement for BCL2 in NK cell survival. In these mice, NK cells in cycle were protected against apoptosis, and NK cell counts were restored in inflammatory conditions, suggesting a redundant role for BCL2 in proliferating NK cells. Consistent with this, cycling NK cells expressed higher MCL1 (myeloid cell leukemia 1) levels in both control and BCL2-null mice. Finally, we showed that deletion of BIM restored survival in BCL2-deficient but not MCL1-deficient NK cells. Overall, these data demonstrate an essential role for the binding of BCL2 to BIM in the survival of noncycling NK cells. They also favor a model in which MCL1 is the dominant survival protein in proliferating NK cells.

PMID:
28057804
PMCID:
PMC5294858
DOI:
10.1084/jem.20160869
[Indexed for MEDLINE]
Free PMC Article

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