Abstract
Natural killer (NK) cells play an important role in anti-tumor immunity. Interleukin (IL)-18 is an immunoregulatory cytokine that induces potent NK cell-dependent anti-tumor responses when administrated with other cytokines. In this study, we explored the effects of combining IL-18 and IL-2 on NK cytotoxicity as well as expression levels of the NK cell receptor NKG2D in vitro. Freshly isolated PBMCs were incubated for 48 h with IL-18 and IL-2, then CD107a expression on CD3-CD56+ NK cells was determined by three-colour flow cytometry to evaluate the cytotoxicity of NK cells against human erythroleukemia K562 cells and human colon carcinoma HT29 cells. Flow cytometric analysis was also employed to determine NKG2D expression on NK cells. The combined use of IL-18 and IL-2 significantly increased CD107a expression on NK cells compared with using IL-18 or IL-2 alone, suggesting that the combination of these two cytokines exerted synergistic enhancement of NK cytotoxicity. IL-18 also enhanced NKG2D expression on NK cells when administered with IL-2. In addition, blockade of NKG2D signaling with NKG2D-blocking antibody attenuated the up-regulatory effect of combining IL-18 and IL-2 on NK cytolysis. Our data revealed that IL-18 synergized with IL-2 to dramatically enhance the cytolytic activity of human NK cells in a NKG2D-dependent manner. The results appear encouraging for the use of combined IL-18 and IL-2 in tumor immunotherapy.
Highlights
Natural killer (NK) cells are a major component of effector lymphocytes in the early host defenses against tumors and infections as they can directly kill target cells without prior stimulation (Vivier et al, 2008)
Isolated Peripheral blood mononuclear cells (PBMCs) were incubated for 48 h with IL-18 and IL-2, CD107a expression on CD3-CD56+ NK cells was determined by three-colour flow cytometry to evaluate the cytotoxicity of NK cells against human erythroleukemia K562 cells and human colon carcinoma HT29 cells
We found that IL-18 synergized with IL-2 to promote the cytotoxicity and NKG2D expression of NK cells
Summary
Natural killer (NK) cells are a major component of effector lymphocytes in the early host defenses against tumors and infections as they can directly kill target cells without prior stimulation (Vivier et al, 2008). Several ligands of NKG2D receptor have been identified to date, including human UL16-binding proteins (ULBPs) and MHC I-related A/B (MICA/B) molecules that are frequently up-regulated on abnormal cells but poorly expressed by healthy adult tissue (Huergo-Zapico et al, 2014). By recognizing and binding to corresponding ligands expressed on tumor cells, NKG2D regulates the activation of effector lymphocytes and plays a vital role in cell-mediated tumor surveilance and elimination (Zafirova et al, 2011; Shen et al, 2012; Yu et al, 2014)
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