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

Heinrich Schlums, Moonjung Jung, Hongya Han, Jakob Theorell, Venetia Bigley, Samuel C.C. Chiang, David S.J. Allan, Jan K. Davidson-Moncada, Rachel E. Dickinson, Tim D. Holmes, Amy P. Hsu, Danielle Townsley, Thomas Winkler, Weixin Wang, Pål Aukrust, Ingvild Nordøy, Katherine R. Calvo, Steve M. Holland, Matthew Collin, Cynthia E. Dunbar and Yenan T. Bryceson

Key points

  • GATA-2 expression is restricted to HSPCs, leading to deficiency of NK cell progenitors in patients with GATA2 mutation.

  • A long-lived or self-renewing pool of adaptive NK cells can persist in patients with GATA2 mutation.


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 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 PLZF, as well as expression of intracellular signaling proteins FcϵRγ, SYK, and 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 IFN-γ upon Fc-receptor engagement but not following combined IL-12 and IL-18 stimulation. Canonical, PLZF-expressing NK cells were retained in asymptomatic carriers of GATA2 mutation. Developmentally, 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 suggests that adaptive NK cells are more long-lived than canonical, immunoregulatory NK cells.

  • Submitted August 18, 2016.
  • Accepted February 2, 2017.