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Plasma membrane lipid scrambling causing phosphatidylserine exposure negatively regulates NK cell activation


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.

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This work was supported by grants from the Canadian Institutes of Health Research (CIHR) MT-14429, MOP-82906, and FDN-143338 to A.V., and NSFC-31870863 from the National Natural Science Foundation of China to N.W. N.W. was supported by a Postdoctoral Fellowship from Fonds de recherche du Québec Santé (FRQS). A.V. is the Canada Research Chair on Signaling in the Immune System.

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Correspondence to Ning Wu or André Veillette.

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Competing interests

A.V. received a contract from Bristol Myers-Squibb to study the mechanism of action of the anti-SLAMF7 monoclonal antibody elotuzumab in multiple myeloma. He was also a consultant for Boehringer-Ingelheim on the topic of the SIRPα-CD47 blockade in anticancer immunotherapy. The authors declare no competing interests.

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Wu, N., Song, H. & Veillette, A. Plasma membrane lipid scrambling causing phosphatidylserine exposure negatively regulates NK cell activation. Cell Mol Immunol 18, 686–697 (2021).

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  • NK cell activation
  • Phosphatidylserine exposure
  • Lipid scrambling
  • TMEM16F
  • Signaling


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