Liu Weiru, Scott Jeannine M, Langguth Emma, Chang Helena, Park Peter H, Kim Sungjin
Center for Comparative Medicine, University of California, Davis, CA 95616, USA.
Biochemistry, Molecular, Cellular and Developmental Biology Graduate Group, University of California, Davis, USA.
iScience. 2020 Oct 20;23(11):101709. doi: 10.1016/j.isci.2020.101709. eCollection 2020 Nov 20.
Adaptive human natural killer (NK) cells display significantly enhanced responsiveness to a broad-range of antibody-bound targets through the engagement of CD16 compared to conventional NK cells, yet direct reactivity against tumor targets is generally reduced. Adaptive NK cells also display a distinct phenotype and differential expression of numerous genes, including reduced expression of signaling adapter FcRγ and transcription factor PLZF. However, it is unclear whether differential expression of specific genes is responsible for the characteristics of adaptive NK cells. Using CRISPR-Cas9, we show deletion of FcRγ in conventional NK cells led to enhanced CD16 responsiveness, abolished cell surface expression of natural cytotoxicity receptors, NKp46 and NKp30, and dramatically reduced responsiveness to K562 and Raji tumor cells. However, deletion of PLZF had no notable effects. These results suggest multiple roles for FcRγ and identify its deficiency as an important factor responsible for the functional and phenotypic characteristics exhibited by adaptive NK cells.
与传统自然杀伤（NK）细胞相比，适应性人类NK细胞通过CD16的参与，对广泛的抗体结合靶标表现出显著增强的反应性，但对肿瘤靶标的直接反应性通常会降低。适应性NK细胞还表现出独特的表型和众多基因的差异表达，包括信号衔接子FcRγ和转录因子PLZF的表达降低。然而，尚不清楚特定基因的差异表达是否是适应性NK细胞特征的原因。使用CRISPR-Cas9，我们发现传统NK细胞中FcRγ的缺失导致CD16反应性增强，自然细胞毒性受体NKp46和NKp30的细胞表面表达消失，以及对K562和Raji肿瘤细胞的反应性显著降低。然而，PLZF的缺失没有显著影响。这些结果表明FcRγ具有多种作用，并确定其缺陷是导致适应性NK细胞表现出功能和表型特征的重要因素。
