Cytokine-enhanced NK cell-mediated cytotoxicity. Positive modulatory effects of IL-2 and IL-12 on stimulus-dependent granule exocytosis

• Published in: The Journal of immunology (1950) Vol. 152; no. 5; pp. 2098 - 2104
• Main Authors: Bonnema, JD, Rivlin, KA, Ting, AT, Schoon, RA, Abraham, RT, Leibson, PJ
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Am Assoc Immnol 01.03.1994; American Association of Immunologists
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Biological and medical sciences; Calcium - metabolism; Cell Line; Cytotoxicity, Immunologic; Exocytosis - immunology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; GTP-Binding Proteins - metabolism; Humans; Immunobiology; Interleukin-12; Interleukin-2 - pharmacology; Interleukins - pharmacology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Killer Cells, Natural - secretion; Lymphokines, interleukins ( function, expression); Protein Kinase C - metabolism; Receptors, Fc - immunology; Regulatory factors and their cellular receptors; Signal Transduction - immunology; Human; Protein kinase C; Calcium; Serine endopeptidases; Enzyme; Immunomodulation; Secretion; Cytokine; β-N-Acetylhexosaminidase; Cytotoxicity; Interleukin 12; Natural killer cell; Cell line; Interleukin 2; Glycosidases; Hydrolases; O-Glycosidases; Proteinases; G protein
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.152.5.2098

NK cells are a subpopulation of lymphocytes that kill virally infected cells and tumor cells without previous sensitization. Although exposure to distinct cytokines, including IL-2 and IL-12, can enhance these cytotoxic responses, the mechanism of this lymphokine-augmented killing remains unclear. Inasmuch as the cytotoxic event is a multistep process, there are many potential targets for lymphokine regulation. We focused on whether selected lymphokines directly modulate the intracellular signaling pathways critical for NK cell secretory function. In our experimental model, homogeneous, cloned human CD16+/CD3- NK cells were pretreated with either IL-2 or IL-12 and then stimulated with direct pharmacologic activators of the secretory response (e.g., PMA and ionomycin for intact cells or GTP gamma S for streptolysin-O permeabilized cells). Previous exposure of the cells to IL-2 or IL-12 enhanced the stimulus-induced release of granule-derived proteins (hexosaminidase and serine proteases) in a cytokine concentration- and time-dependent fashion. Furthermore, the cytokines increased the efficacies without changing the potencies of the secretagogues used in these studies. These results suggest that IL-2 and IL-12 augment NK cell-mediated cytotoxicity by increasing the maximal level of granule exocytosis evoked by Ca2+ and/or G protein-dependent intracellular signaling pathways.