Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56bright subset

• Published in: Blood 2013-04, Vol.121 (14), p.2669-2677
• Main Authors: Mace, Emily M., Hsu, Amy P., Monaco-Shawver, Linda, Makedonas, George, Rosen, Joshua B., Dropulic, Lesia, Cohen, Jeffrey I., Frenkel, Eugene P., Bagwell, John C., Sullivan, John L., Biron, Christine A., Spalding, Christine, Zerbe, Christa S., Uzel, Gulbu, Holland, Steven M., Orange, Jordan S.
• Format: Article
• Language: English
• Subjects: Immunobiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-09-453969

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 CD56bright stage preceding terminal maturation to the CD56dim 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 CD56dim 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 CD56bright cells. Thus, GATA2 is required for the maturation of human NK cells and the maintenance of the CD56bright pool in the periphery. Defects in GATA2 are a novel cause of profound NK cell dysfunction. •Mutations in GATA2 are a cause of human NK cell deficiency.•GATA2 is required for human NK cell maturation, specifically maintenance of the CD56bright subset.