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

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.; Vivier, E.; et al.

doi:10.1084/jem.20160869

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

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hdl_121738.pdf (3.18 MB)

Date

2017

Authors

Viant, C.

Guia, S.

Hennessy, R.J.

Rautela, J.

Pham, K.

Bernat, C.

Goh, W.

Jiao, Y.

Delconte, R.

Roger, M.

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Journal article

Citation

Journal of Experimental Medicine (JEM), 2017; 214(2):491-510

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Charlotte Viant, Sophie Guia, Robert J. Hennessy, Jai Rautela, Kim Pham ... Benjamin T. Kile ... et al.

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10.1084/jem.20160869

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.

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© 2017 Viant et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http ://www .rupress .org /terms /). After six months it is available under a Creative Commons License (Attribution–Noncommercial– Share Alike 4.0 International license, as described at https ://creativecommons .org /licenses /by -nc -sa /4 .0 /).

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https://doi.org/10.1084/jem.20160869

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http://hdl.handle.net/2440/121738

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

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