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

作者：Schlums Heinrich; Jung Moonjung; Han Hongya; Theorell Jakob; Bigley Venetia; Chiang Samuel C C; Allan David S J; Davidson Moncada Jan K; Dickinson Rachel E; Holmes Tim D; Hsu Amy P; Townsley Danielle; Winkler Thomas; Wang Weixin; Aukrust Pal; Nordoy Ingvild; Calvo Katherine R; Holland Steve M; Collin Matthew; Dunbar Cynthia E; Bryceson Yenan T^*

来源：Blood, 2017, 129(14): 1927-1939.

DOI：10.1182/blood-2016-08734236

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 epsilon R gamma, 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-gamma 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(-)CD56(bright), canonical, or adaptive CD3(-)CD56(dim) 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.

• 出版日期2017-4-6