TY - JOUR
T1 - Cell cycle progression dictates the requirement for BCL2 in natural killer cell survival
AU - Viant, Charlotte
AU - Guia, Sophie
AU - Hennessy, Robert J.
AU - Rautela, Jai
AU - Pham, Kim
AU - Bernat, Claire
AU - Goh, Wilford
AU - Jiao, Yuhao
AU - Delconte, Rebecca
AU - Roger, Michael
AU - Simon, Vanina
AU - Souza-Fonseca-Guimaraes, Fernando
AU - Grabow, Stephanie
AU - Belz, Gabrielle T.
AU - Kile, Benjamin T.
AU - Strasser, Andreas
AU - Gray, Daniel
AU - Hodgkin, Phillip D.
AU - Beutler, Bruce
AU - Vivier, Eric
AU - Ugolini, Sophie
AU - Huntington, Nicholas D.
N1 - Funding Information:
We wish to thank Tania Camilleri and Cathy Quillici for assistance and Ana Cumano for helpful discussions. We thank the staff of the WEHI Animal Services, the flow cytometry facility, and the Clinical Translational Centre. We thank the CIML flow cytometry facility and the CIML and CEF OS animal facilities. This work is supported by program and project grants from the National Health and Medical Research Council (NHM RC) of Australia (1049407, 1066770, 1057852, and 1027472 to N.D. Huntington; 1047903 and 1027472 to G.T. Belz; 1078763 to D. Gray; 1016701 to A. Strasser; and 1057831 and 1054925 to K. Pham and P.D. Hodgkin), as well as an NHM RC Independent Research Institute Infrastructure Support Scheme grant and a Victorian State Government Operational Infrastructure Scheme grant. N.D. Huntington is a recipient of a Melanoma Research Grant from the Harry J. Lloyd Charitable Trust and a CLIP grant from Cancer Research Institute. A. Strasser and D. Gray hold a Cancer Council Victoria (CCV) Grant in Aid (1102104). This work is also supported by fellowships from the NHM RC (GNT0461276 to N.D. Huntington, 1090236 to D. Gray, and 1020363 to A. Strasser), the Australian Research Council (to G.T. Belz), the Leukemia and Lymphoma Society (SCOR grant 7413 to A. Strasser and D. Gray), the CCV (1052309 to A. Strasser), and the Menzies Foundation (to N.D. Huntington). This work is also supported by grants from the French Agence Nationale de la Recherche (ANR-JC07-206305 and ANR-08-JCJC-0016) and the European Research Council (THI NK Advanced Grant to E. Vivier) and by institutional grants from Institut National de la Sant? et de la Recherche M?dicale, Centre National de la Recherche Scientifique, and Aix-Marseille Universit? to CIML (S. Ugolini and E. Vivier laboratory). This study was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHM RC Independent Research Institute Infrastructure Support scheme. E. Vivier is a scholar of the Institut Universitaire de France. Whole-exome captures and high-throughput sequencing and analysis were performed at the Transcriptomique et G?nomique de Marseille-Luminy (TGML) Platform, which is supported by grants from IBiSA, Aix-Marseille Universit?, and the "Investissements d'Avenir" program France G?nomique ANR-10-INBS-0009-10. E. Vivier is a co-founder and shareholder in InnatePharma. The remaining authors declare no competing financial interests.
Publisher Copyright:
© 2017 Viant et al.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20160869
DO - 10.1084/jem.20160869
M3 - Article
C2 - 28057804
AN - SCOPUS:85012247261
VL - 214
SP - 491
EP - 510
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 2
ER -