Research ArticleNK CELLS

The transcription factor Bcl11b promotes both canonical and adaptive NK cell differentiation

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Science Immunology  12 Mar 2021:
Vol. 6, Issue 57, eabc9801
DOI: 10.1126/sciimmunol.abc9801

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Human NK cell circuitry

Natural killer (NK) cells are innate immune effector cells that undergo differentiation and education to facilitate protective responses during viral infection and cancer. Holmes et al. performed an integrated transcriptional and epigenetic profiling of human peripheral blood NK cell subsets to construct the transcription factor networks regulating their differentiation. NK cell differentiation converged along an axis that terminated in adaptive NK cells and was progressively regulated by the transcription factor Bcl11b. Ectopic expression of Bcl11b or loss of function in patients harboring BCL11B mutations altered NK cell maturation. Although Bcl11b is known to regulate T cell development, these results identify a complementary role in NK cell differentiation and provide insight into other transcription factors potentially involved in human NK cell identity. See related Focus by Rückert et al. in this issue.


Epigenetic landscapes can provide insight into regulation of gene expression and cellular diversity. Here, we examined the transcriptional and epigenetic profiles of seven human blood natural killer (NK) cell populations, including adaptive NK cells. The BCL11B gene, encoding a transcription factor (TF) essential for T cell development and function, was the most extensively regulated, with expression increasing throughout NK cell differentiation. Several Bcl11b-regulated genes associated with T cell signaling were specifically expressed in adaptive NK cell subsets. Regulatory networks revealed reciprocal regulation at distinct stages of NK cell differentiation, with Bcl11b repressing RUNX2 and ZBTB16 in canonical and adaptive NK cells, respectively. A critical role for Bcl11b in driving NK cell differentiation was corroborated in BCL11B-mutated patients and by ectopic Bcl11b expression. Moreover, Bcl11b was required for adaptive NK cell responses in a murine cytomegalovirus model, supporting expansion of these cells. Together, we define the TF regulatory circuitry of human NK cells and uncover a critical role for Bcl11b in promoting NK cell differentiation and function.

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