活化的人自然杀伤细胞中的复制压力诱导其对细胞凋亡敏感。
Replication Stress in Activated Human NK Cells Induces Sensitivity to Apoptosis.
机构信息
Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY.
Proteomics and Macromolecular Crystallography Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY.
出版信息
J Immunol. 2024 Jul 1;213(1):40-51. doi: 10.4049/jimmunol.2300843.
NK cells are innate immune effectors that kill virally infected or malignant cells. NK cell deficiency (NKD) occurs when NK cell development or function is impaired and variants in MCM4, GINS1, MCM10, and GINS4 result in NKD. Although NK cells are strongly impacted by mutational deficiencies in helicase proteins, the mechanisms underlying this specific susceptibility are poorly understood. In this study, we induced replication stress in activated NK cells or T cells by chemical and genetic methods. We found that the CD56bright subset of NK cells accumulates more DNA damage and replication stress during activation than do CD56dim NK cells or T cells. Aphidicolin treatment increases apoptosis of CD56bright NK cells through increased pan-caspase expression and decreases perforin expression in surviving cells. These findings show that sensitivity to replication stress affects NK cell survival and function and contributes to NKD.
自然杀伤 (NK) 细胞是先天免疫效应细胞，能够杀伤病毒感染或恶性细胞。当 NK 细胞的发育或功能受损时，会发生 NK 细胞缺陷（NKD），并且 MCM4、GINS1、MCM10 和 GINS4 的变异导致 NKD。尽管 NK 细胞受到解旋酶蛋白突变缺陷的强烈影响，但这种特定易感性的机制仍知之甚少。在这项研究中，我们通过化学和遗传方法在活化的 NK 细胞或 T 细胞中诱导复制应激。我们发现，与 CD56dim NK 细胞或 T 细胞相比，NK 细胞的 CD56bright 亚群在激活过程中积累了更多的 DNA 损伤和复制应激。阿非迪可林处理通过增加全胱天冬酶的表达和减少存活细胞中穿孔素的表达来增加 CD56bright NK 细胞的凋亡。这些发现表明，对复制应激的敏感性会影响 NK 细胞的存活和功能，并导致 NKD。
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