Demethylating treatment suppresses natural killer cell cytolytic activity

NK cells as a component of the innate immune system provide a first line of defense against viral infections and malignancies. Killer immunoglobulin-like receptors (KIRs) are a polymorphic gene family expressed on NK cells. The crucial role of DNA methylation in determining the variegated expression pattern of KIRs has recently been reported. In this study the direct effect of DNA demethylating treatment on human NK cell cytotoxicity was analyzed. In a human NK cell line NK-92MI, inhibitory KIR genes exhibited characteristic epigenetic repression, whose promoter regions are densely methylated. Treatment of NK-92MI cells with methyltransferase inhibitor 5-azacytidine significantly increased the expression levels of inhibitory KIRs and strongly suppressed their cytolytic activity against human K562 leukemic cells. Cytolytic activity of human polyclonal NK cells was also suppressed upon 5-azacytidine-treatment. The suppression of NK cell cytotoxicity was associated with 5-azacytidine-induced overexpression of inhibitory KIRs and impaired granzyme B and perforin release by these cells. The results demonstrate for the first time that demethylating treatment can suppress NK cell cytolytic activity. The aberrant methylation patterns of KIR genes during NK cell differentiation and maturation may have importance for its abnormal function.