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 - 2017/1/5
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.
KW - innate immunity and inflammation
KW - tumor immunology
UR - http://www.scopus.com/inward/record.url?scp=85012247261&partnerID=8YFLogxK
U2 - 10.1084/jem.20160869
DO - 10.1084/jem.20160869
M3 - Article
AN - SCOPUS:85012247261
SN - 0022-1007
VL - 214
SP - 491
EP - 510
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 2
ER -