Adaptive NK cells can persist in patients with GATA2 mutation depleted of stem and progenitor cells

Blood. 2017 Apr 6;129(14):1927-1939. doi: 10.1182/blood-2016-08-734236. Epub 2017 Feb 16.


Heterozygous GATA2 mutation is associated with immunodeficiency, lymphedema, and myelodysplastic syndrome. Disease presentation is variable, often coinciding with loss of circulating dendritic cells, monocytes, B cells, and natural killer (NK) cells. Nonetheless, in a proportion of patients carrying GATA2 mutation, NK cells persist. We found that peripheral blood NK cells in symptomatic patients uniformly lacked expression of the transcription factor promyelocytic leukemia zinc finger (PLZF), as well as expression of intracellular signaling proteins FcεRγ, spleen tyrosine kinase (SYK), and EWS/FLI1-Activated Transcript 2 (EAT-2) in a variegated manner. Moreover, consistent with an adaptive identity, NK cells from patients with GATA2 mutation displayed altered expression of cytotoxic granule constituents and produced interferon-γ upon Fc-receptor engagement but not following combined interleukin-12 (IL-12) and IL-18 stimulation. Canonical, PLZF-expressing NK cells were retained in asymptomatic carriers of GATA2 mutation. Developmentally, GATA-binding protein-2 (GATA-2) was expressed in hematopoietic stem cells, but not in NK-cell progenitors, CD3-CD56bright, canonical, or adaptive CD3-CD56dim NK cells. Peripheral blood NK cells from individuals with GATA2 mutation proliferated normally in vitro, whereas lineage-negative progenitors displayed impaired NK-cell differentiation. In summary, adaptive NK cells can persist in patients with GATA2 mutation, even after NK-cell progenitors expire. Moreover, our data suggest that adaptive NK cells are more long-lived than canonical, immunoregulatory NK cells.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Calmodulin-Binding Proteins / genetics
  • Calmodulin-Binding Proteins / immunology
  • Cell Proliferation*
  • Child
  • Female
  • GATA2 Transcription Factor* / genetics
  • GATA2 Transcription Factor* / immunology
  • Hematopoietic Stem Cells / immunology*
  • Humans
  • Interleukin-12 / genetics
  • Interleukin-12 / immunology
  • Interleukin-18 / genetics
  • Interleukin-18 / immunology
  • Killer Cells, Natural / immunology*
  • Male
  • Middle Aged
  • Mutation*
  • RNA-Binding Protein EWS
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / immunology
  • Receptors, IgE / genetics
  • Receptors, IgE / immunology
  • Syk Kinase / genetics
  • Syk Kinase / immunology
  • Transcription Factors / genetics
  • Transcription Factors / immunology


  • Calmodulin-Binding Proteins
  • EWSR1 protein, human
  • FcepsilonRI gamma-chain, human
  • GATA2 Transcription Factor
  • GATA2 protein, human
  • Interleukin-18
  • RNA-Binding Protein EWS
  • RNA-Binding Proteins
  • Receptors, IgE
  • SH2D1B protein, human
  • Transcription Factors
  • Interleukin-12
  • SYK protein, human
  • Syk Kinase