title: Adaptive NK cells can persist in patients withGATA2mutation depleted of stem and progenitor cells.
abstract: HeterozygousGATA2mutation 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 carryingGATA2mutation, 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 withGATA2mutation 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 ofGATA2mutation. 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-CD56dimNK cells. Peripheral blood NK cells from individuals withGATA2mutation proliferated normally in vitro, whereas lineage-negative progenitors displayed impaired NK-cell differentiation. In summary, adaptive NK cells can persist in patients withGATA2mutation, even after NK-cell progenitors expire. Moreover, our data suggest that adaptive NK cells are more long-lived than canonical, immunoregulatory NK cells.
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Schlums
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Moonjung
authors.initials: M
authors.lastname: Jung
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Hongya
authors.initials: H
authors.lastname: Han
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Jakob
authors.initials: J
authors.lastname: Theorell
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Venetia
authors.initials: V
authors.lastname: Bigley
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Samuel C C
authors.initials: SC
authors.lastname: Chiang
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: David S J
authors.initials: DS
authors.lastname: Allan
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Davidson-Moncada
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Dickinson
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.|Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Holmes
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Amy P
authors.initials: AP
authors.lastname: Hsu
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Danielle
authors.initials: D
authors.lastname: Townsley
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Thomas
authors.initials: T
authors.lastname: Winkler
authors.affiliation: Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD; and.
authors.forename: Weixin
authors.initials: W
authors.lastname: Wang
authors.affiliation: Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.affiliation: Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway.
authors.forename: Ingvild
authors.initials: I
authors.lastname: Nordøy
authors.affiliation: Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD; and.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Calvo
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Steve M
authors.initials: SM
authors.lastname: Holland
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Collin
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Cynthia E
authors.initials: CE
authors.lastname: Dunbar
authors.affiliation: Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.|Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway.
authors.forename: Yenan T
authors.initials: YT
authors.lastname: Bryceson
mesh_terms: D000293:Adolescent; D000328:Adult; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002648:Child; D005260:Female; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D017455:Receptors, IgE / Q000235:genetics / Q000276:immunology; D000072377:Syk Kinase / Q000235:genetics / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology
chemical_list: D002148:Calmodulin-Binding Proteins; C500986:EWSR1 protein, human; C543372:FcepsilonRI gamma-chain, human; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D020382:Interleukin-18; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins; D017455:Receptors, IgE; C103572:SH2D1B protein, human; D014157:Transcription Factors; D018664:Interleukin-12; C000606896:SYK protein, human; D000072377:Syk Kinase