Natural Killer Cell Development and Maturation Revisited: Possible Implications of a Novel Distinct Lin(−)CD34(+)DNAM-1(bright)CXCR4(+) Cell Progenitor

Since the first description of natural killer (NK) cells, the view on their role in innate immunity has evolved considerably. In addition to first-line defense against transformed and pathogen-infected autologous cells, NK cells contribute to modulate adaptive immune responses and in some cases acquire specialized functions, including exhausted, adaptive, and decidual NK cells. NK cells derive from CD34(+) progenitors, in vivo and in vitro; however, it is unclear whether the high phenotype diversity in vivo may be generated from these precursors alone. The recent characterization of a novel CD34(+)DNAM-1(bright)CXCR4(+) precursor giving rise to apparently licensed and functional maturing NK cells may suggest the possibility for a higher than expected common lymphocyte precursor diversity and a consequently higher peripheral NK cell phenotype variability. Here, we review the evidences on NK cell central and peripheral development from CD34(+) precursors and propose a possible updated reading frame based on the characterization of CD34(+)DNAM-1(bright)CXCR4(+) cell progenies, which favors the possibility of concurrent NK cell maturation from different CD34(+) precursors.