Transcription factor ID2 prevents E proteins from enforcing a naïve T lymphocyte gene program during NK cell development

Sci Immunol. 2018 Apr 27;3(22):eaao2139. doi: 10.1126/sciimmunol.aao2139.

Abstract

All innate lymphoid cells (ILCs) require the small helix-loop-helix transcription factor ID2, but the functions of ID2 are not well understood in these cells. We show that mature natural killer (NK) cells, the prototypic ILCs, developed in mice lacking ID2 but remained as precursor CD27+CD11b- cells that failed to differentiate into CD27-CD11b+ cytotoxic effectors. We show that ID2 limited chromatin accessibility at E protein binding sites near naïve T lymphocyte-associated genes including multiple chemokine receptors, cytokine receptors, and signaling molecules and altered the NK cell response to inflammatory cytokines. In the absence of ID2, CD27+CD11b- NK cells expressed ID3, a helix-loop-helix protein associated with naïve T cells, and they transitioned from a CD8 memory precursor-like to a naïve-like chromatin accessibility state. We demonstrate that ID3 was required for the development of ID2-deficient NK cells, indicating that completely unfettered E protein function is incompatible with NK cell development. These data solidify the roles of ID2 and ID3 as mediators of effector and naïve gene programs, respectively, and revealed a critical role for ID2 in promoting a chromatin state and transcriptional program in CD27+CD11b- NK cells that supports cytotoxic effector differentiation and cytokine responses.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / immunology*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Chromatin / genetics
  • Chromatin / immunology
  • Chromatin / metabolism
  • Gene Expression Regulation / immunology
  • Inhibitor of Differentiation Protein 2 / genetics
  • Inhibitor of Differentiation Protein 2 / immunology*
  • Inhibitor of Differentiation Protein 2 / metabolism
  • Inhibitor of Differentiation Proteins / genetics
  • Inhibitor of Differentiation Proteins / immunology
  • Inhibitor of Differentiation Proteins / metabolism
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Chromatin
  • Idb2 protein, mouse
  • Inhibitor of Differentiation Protein 2
  • Inhibitor of Differentiation Proteins
  • Tcf3 protein, mouse
  • Idb3 protein, mouse