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

Charlotte Viant, Sophie Guia, Robert J. Hennessy, Jai Rautela, Kim Pham, Claire Bernat, Wilford Goh, Yuhao Jiao, Rebecca Delconte, Michael Roger, Vanina Simon, Fernando Souza-Fonseca-Guimaraes, Stephanie Grabow, Gabrielle T. Belz, Benjamin T. Kile, Andreas Strasser, Daniel Gray, Phillip D. Hodgkin, Bruce Beutler, Eric VivierSophie Ugolini, Nicholas D. Huntington

Research output: Contribution to journalArticle

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)491-510
Number of pages20
JournalJournal of Experimental Medicine
Volume214
Issue number2
DOIs
StatePublished - Jan 1 2017

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Viant, C., Guia, S., Hennessy, R. J., Rautela, J., Pham, K., Bernat, C., Goh, W., Jiao, Y., Delconte, R., Roger, M., Simon, V., Souza-Fonseca-Guimaraes, F., Grabow, S., Belz, G. T., Kile, B. T., Strasser, A., Gray, D., Hodgkin, P. D., Beutler, B., ... Huntington, N. D. (2017). Cell cycle progression dictates the requirement for BCL2 in natural killer cell survival. Journal of Experimental Medicine, 214(2), 491-510. https://doi.org/10.1084/jem.20160869