Sequential actions of EOMES and T-BET promote stepwise maturation of natural killer cells
Jiang Zhang, Stéphanie Le Gras, Kévin Pouxvielh, Fabrice Faure, Lucie Fallone, Nicolas Kern, Marion Moreews, Anne‐Laure Mathieu, Raphaël Schneider, Quentin Marliac, Mathieu Jung, Aurore Berton, Simon Hayek, Pierre‐Olivier Vidalain, Antoine Marçais, Garvin Dodard, Anne S. Dejean, Laurent Brossay, Yad Ghavi-Helm, Thierry Walzer
Abstract
EOMES and T-BET are related T-box transcription factors that control natural killer (NK) cell development. Here we demonstrate that EOMES and T-BET regulate largely distinct gene sets during this process. EOMES is dominantly expressed in immature NK cells and drives early lineage specification by inducing hallmark receptors and functions. 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. Regardless, many genes with distinct functions are co-regulated by the two transcription factors. 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. 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.