title: Cell cycle progression dictates the requirement for BCL2 in natural killer cell survival.
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.
authors.affiliation: 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.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Viant
authors.affiliation: 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.
authors.forename: Sophie
authors.initials: S
authors.lastname: Guia
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hennessy
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors.forename: Jai
authors.initials: J
authors.lastname: Rautela
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors.forename: Kim
authors.initials: K
authors.lastname: Pham
authors.affiliation: 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.
authors.forename: Claire
authors.initials: C
authors.lastname: Bernat
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors.forename: Wilford
authors.initials: W
authors.lastname: Goh
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.|School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Yuhao
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Delconte
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Roger
authors.affiliation: 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.
authors.forename: Vanina
authors.initials: V
authors.lastname: Simon
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors.forename: Fernando
authors.initials: F
authors.lastname: Souza-Fonseca-Guimaraes
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grabow
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gray
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Hodgkin
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
authors.affiliation: 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.|Service Immunologie, Hôpital de la Conception, Assistance Publique Hôpitaux de Marseille (APHM), 13288 Marseille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Vivier
authors.affiliation: 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.
authors.forename: Sophie
authors.initials: S
authors.lastname: Ugolini
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia ugolini@ciml.univ-mrs.fr huntington@wehi.edu.au.|Department of Medical Biology, University of Melbourne, Victoria 3010, Australia.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Huntington
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000502:physiology; D000072224:Bcl-2-Like Protein 11 / Q000502:physiology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002453:Cell Cycle; D002470:Cell Survival; D005260:Female; D007694:Killer Cells, Natural / Q000502:physiology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000950:Antigens, Ly; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D019086:Bridged Bicyclo Compounds, Heterocyclic; D055627:Natural Cytotoxicity Triggering Receptor 1; C118384:Ncr1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C579720:venetoclax