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

作者：Charlotte Viant, Sophie Guia, Robert J. Hennessy, Jai Rautela, Kim Pham, Claire Bernat, Wilford Goh, Yuhao Jiao, Rebecca B. Delconte, M. Macklis Roger, Vanina Simon, Fernando Souza-Fonseca-Guimarães, Stephanie Grabow, Gabrielle T. Belz, Benjamin T. Kile, Andreas Strasser, Daniel H.D. Gray, Philip D. Hodgkin, Bruce Beutler, Éric Vivier, Sophie Ugolini, Nicholas D. Huntington · 发表于：The Journal of Experimental Medicine · 年份：2017 · DOI：10.1084/jem.20160869 · 被引用次数：78 · 研究领域：Immune Cell Function and Interaction、Lymphoma Diagnosis and Treatment、T-cell and B-cell Immunology

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.