Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC, H2W1R7, Canada.
Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China.
Cell Mol Immunol. 2021 Mar;18(3):686-697. doi: 10.1038/s41423-020-00600-9. Epub 2021 Jan 19.
One of the hallmarks of live cells is the asymmetric distribution of lipids across their plasma membrane. Changes in this asymmetry due to lipid "scrambling" result in phosphatidylserine exposure at the cell surface that is detected by annexin V staining. This alteration is observed during cell death processes such as apoptosis, and during physiological responses such as platelet degranulation and membrane repair. Previous studies have shown that activation of NK cells is accompanied by exposure of phosphatidylserine at the cell surface. While this response was thought to be indicative of ongoing NK cell death, it may also reflect the regulation of NK cell activation in the absence of cell death. Herein, we found that NK cell activation was accompanied by rapid phosphatidylserine exposure to an extent proportional to the degree of NK cell activation. Through enforced expression of a lipid scramblase, we provided evidence that activation-induced lipid scrambling in NK cells is reversible and does not lead to cell death. In contrast, lipid scrambling attenuates NK cell activation. This response was accompanied by reduced cell surface expression of activating receptors such as 2B4, and by loss of binding of Src family protein tyrosine kinases Fyn and Lck to the inner leaflet of the plasma membrane. Hence, lipid scrambling during NK cell activation is, at least in part, a physiological response that reduces the NK cell activation level. This effect is due to the ability of lipid scrambling to alter the distribution of membrane-associated receptors and kinases required for NK cell activation.
活细胞的特征之一是其质膜两侧脂质的不对称分布。由于脂质“混合”导致这种不对称性的改变，会导致磷脂酰丝氨酸在细胞表面暴露，这可以通过 annexin V 染色检测到。这种改变发生在细胞死亡过程中，如细胞凋亡，以及生理反应中，如血小板脱颗粒和膜修复。先前的研究表明，NK 细胞的激活伴随着质膜上磷脂酰丝氨酸的暴露。虽然这种反应被认为是 NK 细胞死亡的标志，但它也可能反映了在没有细胞死亡的情况下 NK 细胞激活的调节。在此，我们发现 NK 细胞的激活伴随着磷脂酰丝氨酸的快速暴露，其程度与 NK 细胞的激活程度成正比。通过强制表达一种脂质翻转酶，我们提供了证据表明，激活诱导的 NK 细胞中的脂质翻转是可逆的，不会导致细胞死亡。相比之下，脂质翻转会减弱 NK 细胞的激活。这种反应伴随着激活受体如 2B4 的细胞表面表达减少，以及Src 家族蛋白酪氨酸激酶 Fyn 和 Lck 与质膜内层结合的丧失。因此，NK 细胞激活过程中的脂质翻转至少部分是一种降低 NK 细胞激活水平的生理反应。这种效应是由于脂质翻转能够改变 NK 细胞激活所需的膜相关受体和激酶的分布。
