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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    • "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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    ABSTRACT: Abstract Natural Killer (NK) cells are innate immune effectors that are primarily involved in immunosurveillance to spontaneously eliminate malignantly transformed and virally infected cells without prior sensitization. NK cells trigger targeted attack through release of cytotoxic granules, and secrete various cytokines and chemokines to promote subsequent adaptive immune responses. NK cells selectively attack target cells with diminished major histocompatibility complex (MHC) class I expression. This “Missing-self” recognition by NK cells at first puzzled researchers in the early 1990s, and the mystery was solved with the discovery of germ line encoded killer immunoglobulin receptors that recognize MHC-I molecules. This review summarizes the biology of NK cells detailing the phenotypes, receptors and functions; interactions of NK cells with dendritic cells (DCs), macrophages and T cells. Further we discuss the various strategies to modulate NK cell activity and the practice of NK cells in cancer immunotherapy employing NK cell lines, autologous, allogeneic and genetically engineered cell populations. Keywords NK cells; Cancer; Immunotherapy; Adoptive cell transfer
    Cancer Letters 12/2014; 357(2). DOI:10.1016/j.canlet.2014.12.020 · 5.62 Impact Factor
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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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    ABSTRACT: Natural killer (NK) cells are innate lymphoid cells important for host defense against pathogens and mediate antitumor immunity. Cytokine receptors transduce important signals that regulate proliferation, survival, activation status, and trigger effector functions. Here, we review the roles of major cytokines that regulate human NK cell development, survival, and function, including IL-2, IL-12, IL-15, IL-18, and IL-21, and their translation to the clinic as immunotherapy agents. We highlight a recent development in NK cell biology, the identification of innate NK cell memory, and focus on cytokine-induced memory-like (CIML) NK cells that result from a brief, combined activation with IL-12, IL-15, and IL-18. This activation results in long lived NK cells that exhibit enhanced functionality when they encounter a secondary stimulation and provides a new approach to enable NK cells for enhanced responsiveness to infection and cancer. An improved understanding of the cellular and molecular aspects of cytokine-cytokine receptor signals has led to a resurgence of interest in the clinical use of cytokines that sustain and/or activate NK cell antitumor potential. In the future, such strategies will be combined with negative regulatory signal blockade and enhanced recognition to comprehensively enhance NK cells for immunotherapy.
    06/2014; DOI:10.1155/2014/205796
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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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    ABSTRACT: Natural Killer (NK) cells are innate lymphocytes with an important role in the early defense against intracellular pathogens and against tumors. Like other immune cells, almost every aspects of their biology are regulated by cytokines. Interleukin (IL)-15 is pivotal for their development, homeostasis, and activation. Moreover, numerous other activating or inhibitory cytokines such as IL-2, IL-4, IL-7, IL-10, IL-12, IL-18, IL-21, Transforming growth factor-β (TGFβ) and type I interferons regulate their activation and their effector functions at different stages of the immune response. In this review we summarize the current understanding on the effect of these different cytokines on NK cell development, homeostasis, and functions during steady-state or upon infection by different pathogens. We try to delineate the cellular sources of these cytokines, the intracellular pathways they trigger and the transcription factors they regulate. We describe the known synergies or antagonisms between different cytokines and highlight outstanding questions in this field of investigation. Finally, we discuss how a better knowledge of cytokine action on NK cells could help improve strategies to manipulate NK cells in different clinical situations.
    Frontiers in Immunology 12/2013; 4:450. DOI:10.3389/fimmu.2013.00450
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