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) subset

• Human NK cells can be divided into CD56dim and CD56bright subsets. These two types of NK cells respond to different types of stimuli, with CD56dim NK cells having direct cytotoxic ability and CD56bright NK cells having mainly an immunoregulatory function. We show that the CD16+CD56dim 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 CD56dim NK cells, because the ability of granulocytes to kill CD56dim NK cells was completely abrogated in the presence of the hydrogen peroxide scavenger catalase. When exposing NK cells to H2O2, CD56dim cells showed rapid mitochondrial depolarization and down-regulation of activating NKRs, eventually resulting in cell death, whereas CD56bright cells remained unaffected. The difference in sensitivity to H2O2 was mirrored by a difference in intracellular oxidation levels between CD56dim and CD56bright 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 CD56bright NK cells often seen in environments rich in reactive oxygen species, such as at sites of chronic inflammation and in tumors.

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