TY - JOUR
T1 - Adaptive NK cells can persist in patients with GATA2 mutation depleted of stem and progenitor cells
AU - Schlums, Heinrich
AU - Jung, Moonjung
AU - Han, Hongya
AU - Theorell, Jakob
AU - Bigley, Venetia
AU - Chiang, Samuel C.C.
AU - Allan, David S.J.
AU - Davidson-Moncada, Jan K.
AU - Dickinson, Rachel E.
AU - Holmes, Tim D.
AU - Hsu, Amy P.
AU - Townsley, Danielle
AU - Winkler, Thomas
AU - Wang, Weixin
AU - Aukrust, Pål
AU - Nordøy, Ingvild
AU - Calvo, Katherine R.
AU - Holland, Steve M.
AU - Collin, Matthew
AU - Dunbar, Cynthia E.
AU - Bryceson, Yenan T.
N1 - Funding Information:
This work was supported by the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC grant agreement no. 311335, Swedish Research Council, Norwegian Research Council, Swedish Foundation for Strategic Research, Wallenberg Foundation, Swedish Cancer Foundation, Swedish Childhood Cancer Foundation, as well as the Stockholm County Council and Karolinska Institutet Center for
Publisher Copyright:
© 2017, American Society of Hematology. All rights reserved.
PY - 2017/4/6
Y1 - 2017/4/6
N2 - 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 Fc«Rg, 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-g 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, CD32CD56bright, canonical, or adaptive CD32CD56dim 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.
AB - 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 Fc«Rg, 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-g 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, CD32CD56bright, canonical, or adaptive CD32CD56dim 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.
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U2 - 10.1182/blood-2016-08-734236
DO - 10.1182/blood-2016-08-734236
M3 - Article
C2 - 28209719
AN - SCOPUS:85018925030
SN - 0006-4971
VL - 129
SP - 1927
EP - 1939
JO - Blood
JF - Blood
IS - 14
ER -