Interleukin‐21 differentially affects human natural killer cell subsets

Abstract

Interleukin-21 (IL-21) is a cytokine with pleiotropic effects on various cell types including dendritic cells, B cells, T cells and natural killer (NK) cells. To evaluate if IL-21 affects human NK cell subpopulations in a similar fashion, functional studies were performed on CD56^dim and CD56^bright NK cells, both bearing IL-21 receptors at identical densities. Stimulation with IL-21 strongly induced proliferation of CD56^bright NK cells and cytotoxicity against K562 target cells was preferentially augmented in CD56^dim NK cells. In contrast, stimulation with IL-2 and IL-21 alone or in combination failed to induce interferon-γ and tumour necrosis factor-α production in the two NK cell subsets. Intracellular analysis of signal transducer and activator of transcription (STAT) proteins revealed that IL-21 by itself induces phosphorylation of STAT1 and STAT3 in CD56^dim NK cells, and to an even higher degree in CD56^bright NK cells. In this CD56^bright NK cell population alone, IL-2 weakly phosphorylated STAT1 and STAT3, which was further increased when cells were treated with the combination of both cytokines. In contrast, STAT5 was strongly phosphorylated only in CD56^bright NK cells by low-dose IL-2, while IL-21 did not affect STAT5 at all. In summary, we present data indicating that the NK-cell-directed cytokines IL-2 and IL-21 not only affect functions in NK cell subpopulations differently but can also act additively.