Cutting edge: Priming of NK cells by IL-18

Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Institut National de la Santé et de la Recherche Médicale Unité, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6102, Marseille, France
The Journal of Immunology (Impact Factor: 4.92). 08/2008; 181(3):1627-31. DOI: 10.4049/jimmunol.181.3.1627
Source: PubMed


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

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Available from: Thierry Walzer
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    • "Likewise, IL-12 and IL-18 combination exerts cooperative effects on NK cell-mediated cytotoxicity, IFN-γ secretion and proliferation [59]. This is supported by the evidence that NK cells from IL-18R –/– mice cannot secrete INF-γ upon stimulation with IL- 12, which implies that IL-18 signaling has an important role to make NK cells responsive to IL-12 [50] [60]. Additionally, the combination of IL-12 and IL-15 or IL-15 and IL-18 also promotes a robust secretion of IFN-γ, IL-10, MIP-1α, TNF-α and GM-SCF [61]. "
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    • "However, the IL-18Rα is constitutively expressed on unstimulated NK cells and can induce NK cell proliferation alone, although the addition of IL-15 greatly enhances proliferation [120]. Other distinct roles for IL-18 include reports that dendritic cell-derived IL-18 primes NK cells to produce more IFN-γ during later stimulation [42]. Additionally, NK cells from IL-18 deficient mice have impaired cytotoxicity and IFN-γ production, indicating the importance of this cytokine to NK mediated host defense [122]. "
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    • "IL-18 is critical for IFN-γ production by NK cells during numerous bacterial (165), fungal (166), parasites (127), and viral (167) infections. In addition to regulating IFN-γ production, IL-18 takes part to the priming of NK cells (29, 168), and leads to the acquisition of novel migratory function through up-regulation of CCR7 (155, 169). It has also been shown that IL-18 induces the release of CC chemokine Ligand 3 (CCL3) by NK cells, which in turns recruits inflammatory monocytes in the intestine and contribute to local inflammation (170). "
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