NK cells gain higher IFN-γ competence during terminal differentiation

NK cells are the main cells of the innate immune system that produce IFN-gamma, and they express this cytokine at early stages of maturation in response to cytokine stimulation. Conversely, acquisition of IFN-gamma-competence in CD4(+) T helper cells requires a differentiation process from naive toward type 1 (Th1) cells, which is associated with epigenetic remodeling at the IFNG locus. In the present study, we show that the ability of NK cells to produce IFN-gamma in response to activating receptor (actR) engagement is gradually acquired during terminal differentiation and is accompanied by progressively higher NF-kappa B activation in response to actR triggering. Moreover, during the differentiation process NK cells gradually display increasing expression of IFNG and TBX21 (encoding T-bet) transcripts and demethylation at the IFNG promoter. This study provides new insights in the molecular mechanisms underlying NK-cell ability to express IFN-gamma upon actR engagement. Thus, we propose that in order to efficiently produce IFN-gamma in response to infected or transformed cells, NK cells gain Th1-like features, such as higher IFN-gamma competence and epigenetic remodeling of the IFNG promoter, during their terminal differentiation.