Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56(bright) subset.
Mutations in the transcription factor GATA2 underlie the syndrome of monocytopenia and B- and natural killer (NK)-cell lymphopenia associated with opportunistic infections and cancers. In addition, patients have recurrent and severe viral infections. NK cells play a critical role in mediating antiviral immunity. Human NK cells are thought to mature in a linear fashion, with the CD56(bright) stage preceding terminal maturation to the CD56(dim) stage, considered the most enabled for cytotoxicity. Here we report an NK cell functional defect in GATA2-deficient patients and extend this genetic lesion to what is considered to be the original NK cell-deficient patient. In most cases, GATA2 deficiency is accompanied by a severe reduction in peripheral blood NK cells and marked functional impairment. The NK cells detected in peripheral blood of some GATA2-deficient patients are exclusively of the CD56(dim) subset, which is recapitulated on in vitro NK cell differentiation. In vivo, interferon α treatment increased NK cell number and partially restored function but did not correct the paucity of CD56(bright) cells. Thus, GATA2 is required for the maturation of human NK cells and the maintenance of the CD56(bright) pool in the periphery. Defects in GATA2 are a novel cause of profound NK cell dysfunction.
Baylor College of Medicine, Houston, TX, USA.
Emily M
EM
Mace
Amy P
AP
Hsu
Linda
L
Monaco-Shawver
George
G
Makedonas
Joshua B
JB
Rosen
Lesia
L
Dropulic
Jeffrey I
JI
Cohen
Eugene P
EP
Frenkel
John C
JC
Bagwell
John L
JL
Sullivan
Christine A
CA
Biron
Christine
C
Spalding
Christa S
CS
Zerbe
Gulbu
G
Uzel
Steven M
SM
Holland
Jordan S
JS
Orange
D018952:Antigens, CD34 / Q000378:metabolism; D019002:CD56 Antigen / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D050989:GATA2 Transcription Factor / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D018952:Antigens, CD34; D019002:CD56 Antigen; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C522918:NCAM1 protein, human