Human natural killer cells with polyclonal lectin and immunoglobulinlike receptors develop from single hematopoietic stem cells with preferential expression of NKG2A and KIR2DL2/L3/S2

The stage of progenitor maturation and factors that determine the fate and clonal acquisition of human natural killer (NK) cell receptors during devel opment are unknown. To study human NK cell receptor ontogeny, umbilical cor d blood CD34(+)/ Lin(-)/CD38(-) cells were cultured with a murine fetal liv er line (AFT024) and defined cytokines. In the absence of lymphocyte-stimul ating cytokines or when contact with AFT024 was prohibited, NK cell progeny were killer immunoglobulinlike receptor (KIR) and CD94 lectin receptor neg ative. In contrast, efficient NK cell differentiation and receptor acquisit ion was dependent on direct contact of progenitors with AFT024 and the addi tion of interieukin-15 (IL-15) or IL-2 but not IL-7. To address the questio n of whether receptor acquisition was determined at the stem cell level, si ngle CD34(+)/Lin(-)/CD38(-) progenitors were studied. More than 400 single cell progeny were analyzed from cultures containing IL-15 or IL-2 and NK ce lls were always polyclonal, suggesting that receptor fate is determined bey ond an uncommitted progenitor and that receptor-negative NK cells acquire c lass I-recognizing receptors after lineage commitment. KIR2DL2/L3/S2 was ex pressed more than KIR2DL1/S1 or KIR3DL1, and NKG2A was the dominant CD94 re ceptor, independent of whether the stem cell source contained the respectiv e major histocompatibility complex class I ligand, suggesting a nonrandom s equence of receptor acquisition. The conclusion is that NK receptor fate is determined after NK cell commitment, does not require stromal presentation of human class I alleles, and is clonally stable after expression but dyna mic because new receptors are acquired over time. (C) 2001 by The American Society of Hematology.