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 Vivier & 2 others Sophie Ugolini, Nicholas D. Huntington

Research output: Contribution to journalArticleResearchpeer-review

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
Pages (from-to)491-510
Number of pages20
JournalJournal of Experimental Medicine
Volume214
Issue number2
DOIs
Publication statusPublished - 5 Jan 2017
Externally publishedYes

Keywords

  • innate immunity and inflammation
  • tumor immunology

Cite this

Viant, Charlotte ; Guia, Sophie ; Hennessy, Robert J. ; Rautela, Jai ; Pham, Kim ; Bernat, Claire ; Goh, Wilford ; Jiao, Yuhao ; Delconte, Rebecca ; Roger, Michael ; Simon, Vanina ; Souza-Fonseca-Guimaraes, Fernando ; Grabow, Stephanie ; Belz, Gabrielle T. ; Kile, Benjamin T. ; Strasser, Andreas ; Gray, Daniel ; Hodgkin, Phillip D. ; Beutler, Bruce ; Vivier, Eric ; Ugolini, Sophie ; Huntington, Nicholas D. / Cell cycle progression dictates the requirement for BCL2 in natural killer cell survival. In: Journal of Experimental Medicine. 2017 ; Vol. 214, No. 2. pp. 491-510.
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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.",
keywords = "innate immunity and inflammation, tumor immunology",
author = "Charlotte Viant and Sophie Guia and Hennessy, {Robert J.} and Jai Rautela and Kim Pham and Claire Bernat and Wilford Goh and Yuhao Jiao and Rebecca Delconte and Michael Roger and Vanina Simon and Fernando Souza-Fonseca-Guimaraes and Stephanie Grabow and Belz, {Gabrielle T.} and Kile, {Benjamin T.} and Andreas Strasser and Daniel Gray and Hodgkin, {Phillip D.} and Bruce Beutler and Eric Vivier and Sophie Ugolini and Huntington, {Nicholas D.}",
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Viant, C, Guia, S, Hennessy, RJ, Rautela, J, Pham, K, Bernat, C, Goh, W, Jiao, Y, Delconte, R, Roger, M, Simon, V, Souza-Fonseca-Guimaraes, F, Grabow, S, Belz, GT, Kile, BT, Strasser, A, Gray, D, Hodgkin, PD, Beutler, B, Vivier, E, Ugolini, S & Huntington, ND 2017, 'Cell cycle progression dictates the requirement for BCL2 in natural killer cell survival' Journal of Experimental Medicine, vol. 214, no. 2, pp. 491-510. https://doi.org/10.1084/jem.20160869

Cell cycle progression dictates the requirement for BCL2 in natural killer cell survival. / Viant, Charlotte; Guia, Sophie; Hennessy, Robert J.; Rautela, Jai; Pham, Kim; Bernat, Claire; Goh, Wilford; Jiao, Yuhao; Delconte, Rebecca; Roger, Michael; Simon, Vanina; Souza-Fonseca-Guimaraes, Fernando; Grabow, Stephanie; Belz, Gabrielle T.; Kile, Benjamin T.; Strasser, Andreas; Gray, Daniel; Hodgkin, Phillip D.; Beutler, Bruce; Vivier, Eric; Ugolini, Sophie; Huntington, Nicholas D.

In: Journal of Experimental Medicine, Vol. 214, No. 2, 05.01.2017, p. 491-510.

Research output: Contribution to journalArticleResearchpeer-review

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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.

PY - 2017/1/5

Y1 - 2017/1/5

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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KW - tumor immunology

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