Tumor necrosis factor-α enhances IL-15-induced natural killer cell differentiation

The differentiation of natural killer (NK) cells is regulated by various factors including soluble growth factors and transcription factors. Here, we have demonstrated that tumor necrosis factor-α (TNF-α) is a positive regulator of NK cell differentiation. TNF-α augmented the IL-15-induced expression of NK1.1 and CD122 in mature NK cells, and TNF-α alone also induced NK cell maturation as well as IL-15. TNF-α also increased IFN-γ production in NK cells in the presence of IL-15. Meanwhile, mRNA expression of several transcription factors, including T-bet and GATA-3, was increased by the addition of TNF-α and IL-15. In addition, TNF-α increased nuclear factor-kappa B (NF-κB) activity in NK cells and inhibition of NF-κB impeded TNF-α-enhanced NK cell maturation. Overall, these data suggest that TNF-α significantly increased IL-15-driven NK cell differentiation by increasing the expression of transcription factors that play crucial roles in NK cell maturation and inducing the NF-κB activity.