Gene Deregulation and Chronic Activation in Natural Killer Cells Deficient in the Transcription Factor ETS1

SummaryMultiple transcription factors guide the development of mature functional natural killer (NK) cells, yet little is known about their function. We used global gene expression and genome-wide binding analyses combined with developmental and functional studies to unveil three roles for the ETS1 transcription factor in NK cells. ETS1 functions at the earliest stages of NK cell development to promote expression of critical transcriptional regulators including T-BET and ID2, NK cell receptors (NKRs) including NKp46, Ly49H, and Ly49D, and signaling molecules essential for NKR function. As a consequence, Ets1−/− NK cells fail to degranulate after stimulation through activating NKRs. Nonetheless, these cells are hyperresponsive to cytokines and have characteristics of chronic stimulation including increased expression of inhibitory NKRs and multiple activation-associated genes. Therefore, ETS1 regulates a broad gene expression program in NK cells that promotes target cell recognition while limiting cytokine-driven activation.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (223 K)Download as PowerPoint slideHighlights► The essential NK cell genes Tbx21 and Idb2 are direct targets of ETS1 ► ETS1 is required for expression and function of multiple activating NK cell receptors ► ETS1 prevents chronic activation of NK cells ► ETS1-deficient NK cells are hyperresponsive to interleukin 15