<scp>NK</scp> cells gain higher <scp>IFN</scp> ‐γ competence during terminal differentiation

<jats:p> <jats:styled-content style="fixed-case">NK</jats:styled-content> cells are the main cells of the innate immune system that produce <jats:styled-content style="fixed-case">IFN</jats:styled-content> ‐γ, and they express this cytokine at early stages of maturation in response to cytokine stimulation. Conversely, acquisition of <jats:styled-content style="fixed-case">IFN</jats:styled-content> ‐γ‐competence in <jats:styled-content style="fixed-case">CD</jats:styled-content> 4 <jats:sup>+</jats:sup> <jats:styled-content style="fixed-case">T</jats:styled-content> helper cells requires a differentiation process from naïve toward type 1 ( <jats:styled-content style="fixed-case">T</jats:styled-content> h1) cells, which is associated with epigenetic remodeling at the <jats:italic> <jats:styled-content style="fixed-case">IFNG</jats:styled-content> </jats:italic> locus. In the present study, we show that the ability of <jats:styled-content style="fixed-case">NK</jats:styled-content> cells to produce <jats:styled-content style="fixed-case">IFN</jats:styled-content> ‐γ in response to activating receptor (act <jats:styled-content style="fixed-case">R</jats:styled-content> ) engagement is gradually acquired during terminal differentiation and is accompanied by progressively higher <jats:styled-content style="fixed-case">NF</jats:styled-content> ‐κ <jats:styled-content style="fixed-case">B</jats:styled-content> activation in response to act <jats:styled-content style="fixed-case">R</jats:styled-content> triggering. Moreover, during the differentiation process <jats:styled-content style="fixed-case">NK</jats:styled-content> cells gradually display increasing expression of <jats:italic> <jats:styled-content style="fixed-case">IFNG</jats:styled-content> </jats:italic> and <jats:italic> <jats:styled-content style="fixed-case">TBX</jats:styled-content> 21 </jats:italic> (encoding <jats:styled-content style="fixed-case">T</jats:styled-content> ‐bet) transcripts and demethylation at the <jats:italic> <jats:styled-content style="fixed-case">IFNG</jats:styled-content> </jats:italic> promoter. This study provides new insights in the molecular mechanisms underlying <jats:styled-content style="fixed-case">NK</jats:styled-content> ‐cell ability to express <jats:styled-content style="fixed-case">IFN</jats:styled-content> ‐γ upon act <jats:styled-content style="fixed-case">R</jats:styled-content> engagement. Thus, we propose that in order to efficiently produce <jats:styled-content style="fixed-case">IFN</jats:styled-content> ‐γ in response to infected or transformed cells, <jats:styled-content style="fixed-case">NK</jats:styled-content> cells gain <jats:styled-content style="fixed-case">T</jats:styled-content> h1‐like features, such as higher <jats:styled-content style="fixed-case">IFN</jats:styled-content> ‐γ competence and epigenetic remodeling of the <jats:italic> <jats:styled-content style="fixed-case">IFNG</jats:styled-content> </jats:italic> promoter, during their terminal differentiation. </jats:p>