CD56^bright Human NK Cells Differentiate into CD56^dim Cells: Role of Contact with Peripheral Fibroblasts

Abstract

Human NK cells are divided into CD56^brightCD16⁻ cells and CD56^dimCD16⁺ cells. We tested the hypothesis that CD56^bright NK cells can differentiate into CD56^dim cells by prospectively isolating and culturing each NK subset in vitro and in vivo. Our results show that CD56^bright cells can differentiate into CD56^dim both in vitro, in the presence of synovial fibroblasts, and in vivo, upon transfer into NOD-SCID mice. In vitro, this differentiation was inhibited by fibroblast growth factor receptor-1 Ab, demonstrating a role of the CD56 and fibroblast growth factor receptor-1 interaction in this process. Differentiated CD56^dim cells had reduced IFN-γ production but increased perforin expression and cytolysis of cell line K562 targets. Flow cytometric fluorescent in situ hybridization demonstrated that CD56^bright NK cells had longer telomere length compared with CD56^dim NK cells, implying the former are less mature. Our data support a linear differentiation model of human NK development in which immature CD56^bright NK cells can differentiate into CD56^dim cells.