Sequential actions of EOMES and T-BET promote stepwise maturation of natural killer cells

Nat Commun. 2021 Sep 14;12(1):5446. doi: 10.1038/s41467-021-25758-2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / immunology
  • CD11b Antigen / genetics
  • CD11b Antigen / immunology
  • Cell Cycle / drug effects
  • Cell Cycle / genetics*
  • Cell Cycle / immunology
  • Cell Differentiation
  • Cell Lineage / drug effects
  • Cell Lineage / genetics*
  • Cell Lineage / immunology
  • Epigenesis, Genetic / immunology
  • Interleukin-12 / pharmacology
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Promoter Regions, Genetic
  • Protein Binding
  • Spleen / cytology
  • Spleen / immunology
  • T-Box Domain Proteins / deficiency
  • T-Box Domain Proteins / genetics*
  • T-Box Domain Proteins / immunology
  • Transcription, Genetic
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / genetics
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / immunology


  • CD11b Antigen
  • Eomes protein, mouse
  • Itgam protein, mouse
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • Interleukin-12