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
Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille Université, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), 13288 Marseille, France.
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
J Exp Med. 2017 Feb;214(2):491-510. doi: 10.1084/jem.20160869. Epub 2017 Jan 5.
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.
自然杀伤（NK）细胞是具有抗肿瘤功能的先天性淋巴细胞。通过在小鼠中进行N-乙基-N-亚硝基脲（ENU）诱导的诱变筛选，我们鉴定出一种由于Bcl2（B细胞淋巴瘤2）基因的低表达突变而导致NK细胞缺陷的品系。对这些小鼠的分析以及NK细胞中Bcl2的条件性缺失揭示了BCL2在NK细胞存活中具有非冗余的内在需求。在这些小鼠中，处于细胞周期的NK细胞受到保护而免于凋亡，并且在炎症条件下NK细胞计数得以恢复，这表明BCL2在增殖的NK细胞中具有冗余作用。与此一致的是，在对照小鼠和BCL2基因敲除小鼠中，处于细胞周期的NK细胞均表达更高水平的MCL1（髓样细胞白血病1）。最后，我们表明删除BIM可恢复BCL2缺陷而非MCL1缺陷的NK细胞的存活。总体而言，这些数据证明了BCL2与BIM的结合在非循环NK细胞存活中起着至关重要的作用。它们还支持一种模型，即MCL1是增殖的NK细胞中的主要存活蛋白。
