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The CD16^–CD56^bright NK Cell Subset Is Resistant to Reactive Oxygen Species Produced by Activated Granulocytes and Has Higher Antioxidative Capacity Than the CD16⁺CD56^dim Subset¹

Helena Harlin^2,*, Mikael Hanson^2,*, C. Christian Johansson^*, Daiju Sakurai^*, Isabel Poschke^*, Håkan Norell^*, Karl-Johan Malmberg and Rolf Kiessling^3,*

^* Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden; and Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden

Human NK cells can be divided into CD56^dim and CD56^bright subsets. These two types of NK cells respond to different types of stimuli, with CD56^dim NK cells having direct cytotoxic ability and CD56^bright NK cells having mainly an immunoregulatory function. We show that the CD16⁺CD56^dim NK subset is characterized by sensitivity to cell death induced by activated granulocytes. We identified hydrogen peroxide (H₂O₂) as the major effector molecule responsible for the cytotoxic effect of granulocytes on CD56^dim NK cells, because the ability of granulocytes to kill CD56^dim NK cells was completely abrogated in the presence of the hydrogen peroxide scavenger catalase. When exposing NK cells to H₂O₂, CD56^dim cells showed rapid mitochondrial depolarization and down-regulation of activating NKRs, eventually resulting in cell death, whereas CD56^bright cells remained unaffected. The difference in sensitivity to H₂O₂ was mirrored by a difference in intracellular oxidation levels between CD56^dim and CD56^bright NK cells, and cell lysates from the latter subset possessed a greater ability to block H₂O₂-mediated oxidation. Our data may explain the preferential accumulation of CD56^bright NK cells often seen in environments rich in reactive oxygen species, such as at sites of chronic inflammation and in tumors.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants to R.K. from the Swedish Cancer Society, the Cancer Society of Stockholm, the European Union, the Karolinska Institutet, an "ALF-Project" grant from the Stockholm City Council, and National Institutes of Health Grant CA102280. K.-J.M. was supported by the Royal Swedish Academy of Sciences, the Cancer Society of Stockholm, the Swedish Children’s Cancer Foundation, and the Tobias Foundation.

² H.H. and M.H. contributed equally to the work.

³ Address correspondence and reprint requests to Dr. Rolf Kiessling, Department of Oncology and Pathology, Karolinska University Hospital, Solna, CCK R8:01, 171 76 Stockholm, Sweden. E-mail address: Rolf.Kiessling{at}ki.se

⁴ Abbreviations used in this paper: ROS, reactive oxygen species; 7-AAD, 7-aminoactinomycin D; FSC, forward scatter; SSC, side scatter; CM-H₂DCFDA, 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester; SNP, sodium nitroprusside; DCF, fluorescent dichlorofluorescein; HVA, homovanillic acid; DiOC₆(3), 3,3'-dihexyloxacarbocyanine iodide.