Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 214, Issue 2, Pages 491-510Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20160869
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Funding
- National Health and Medical Research Council (NHMRC) of Australia [1049407, 1066770, 1057852, 1027472, 1047903, 1078763, 1016701, 1057831, 1054925]
- NHMRC Independent Research Institute Infrastructure Support Scheme grant
- Victorian State Government Operational Infrastructure Scheme grant
- Harry J. Lloyd Charitable Trust
- Cancer Research Institute
- Cancer Council Victoria (CCV) [1102104]
- NHMRC [GNT0461276, 1090236, 1020363]
- Australian Research Council
- Leukemia and Lymphoma Society (SCOR) [7413]
- CCV [1052309]
- Menzies Foundation
- French Agence Nationale de la Recherche [ANR-JC07-206305, ANR-08-JCJC-0016]
- European Research Council (THINK Advanced Grant)
- Institut National de la Sante et de la Recherche Medicale
- Centre National de la Recherche Scientifique
- Aix-Marseille Universite
- Victorian State Government Operational Infrastructure Support
- Australian Government NHM RC Independent Research Institute Infrastructure Support scheme
- IBiSA
- Investissements d'Avenir program France Genomique [ANR-10-INBS-0009-10]
- National Breast Cancer Foundation [PF-15-008] Funding Source: researchfish
- National Health and Medical Research Council of Australia [1090236, 1057831] Funding Source: NHMRC
- Agence Nationale de la Recherche (ANR) [ANR-08-JCJC-0016] Funding Source: Agence Nationale de la Recherche (ANR)
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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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