Moreover, NK cells and ILC1s are developmentally distinct.

In particular, CD49B and CD49A are expressed in a mutually exclusive manner by NK cells and ILC1s, respectively 4, 5. However, they differ from ILC1s by their capacity to circulate in the blood, by their expression of multiple receptors of the Ly49 family, by their higher cytotoxic potential and by their expression of integrin subunits. NK cells share many features with tissue-resident ILC1s, such as the responsiveness to IL-15, IL-12 and IL-18, and the capacity to rapidly produce IFN-γ upon stimulation 3. Natural Killer (NK) cells are group 1 innate lymphoid cells (ILCs) with an important role in antiviral 1 and anti-tumor responses 2. Our data thus suggest that EOMES and T-BET may distinctly govern, via differential expression and co-factors recruitment, NK cell maturation by inserting partially overlapping epigenetic regulations. By generating two gene-modified mice facilitating chromatin immunoprecipitation of endogenous EOMES and T-BET, we show a strong overlap in their DNA binding targets, as well as extensive epigenetic changes during NK cell differentiation. Regardless, many genes with distinct functions are co-regulated by the two transcription factors. By contrast, T-BET is dominant in mature NK cells, where it induces responsiveness to IL-12 and represses the cell cycle, likely through transcriptional repressors. EOMES is dominantly expressed in immature NK cells and drives early lineage specification by inducing hallmark receptors and functions. Here we demonstrate that EOMES and T-BET regulate largely distinct gene sets during this process. EOMES and T-BET are related T-box transcription factors that control natural killer (NK) cell development.

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