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Recent evidence suggests that NK cells require priming to display full effector activity. Here, we demonstrate that IL-18 contributed to this phenomenon. IL-18 signalling-deficient NK cells were found to be unable to secrete IFN-γ in response to ex vivo stimulation with IL-12. This was not due to a co-stimulatory role of IL-18 because blocking IL-18 signalling during the ex vivo stimulation with IL-12 did not alter IFN-γ production by wild-type NK cells. Rather, we demonstrate that IL-18 primes NK cells in vivo to produce IFN-γ upon subsequent stimulation with IL-12. Importantly, IL-12-induced IFN-γ transcription by NK cells was comparable in IL-18 signalling-deficient and -sufficient NK cells. This suggests that priming by IL-18 leads to an improved translation of IFN-γ mRNA. These results reveal a novel type of cooperation between IL-12 and IL-18 that requires the sequential action of these cytokines.

Key Points• Blockade of inhibitory KIRs with MHC class I antigens on lymphoma cells by anti-KIR antibodies augments NK-cell spontaneous cytotoxicity.• In combination with anti-CD20 mAbs, anti-KIR induces enhanced NK cell-mediated, rituximab-dependent cytotoxicity against lymphoma.