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 a 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.