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

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Science Immunology  27 Apr 2018:
Vol. 3, Issue 22, eaao2139
DOI: 10.1126/sciimmunol.aao2139

Establishing NK cell IDentity

The transcription factor ID2 is required for normal differentiation of all innate lymphoid cells, including natural killer (NK) cells. Zook et al. have characterized ID2-deficient NK cells and investigated how ID2 supports full maturation of NK cells into cytotoxic effectors. They found that ID2 limited chromatin accessibility at multiple lymphocyte-associated genes correlated with a naïve gene program, thereby enabling an effector gene program to take hold. This study provides insight into the series of transcriptional programming steps that underpin normal NK cell differentiation.


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 CD27CD11b+ 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.

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