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 language | English (US) |
|---|---|
| Pages (from-to) | 491-510 |
| Number of pages | 20 |
| Journal | Journal of Experimental Medicine |
| Volume | 214 |
| Issue number | 2 |
| DOIs | |
| State | Published - 2017 |
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ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
Cite this
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, 2017, p. 491-510.Research output: Contribution to journal › Article
}
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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85012247261&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85012247261&partnerID=8YFLogxK
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 -