The Axl/Gas6 Pathway Is Required for Human Natural Killer Cell Development.

Natural killer (NK) cells play an important role in host defense against microbial infection and tumors. Previous studies showed that IL-15 is essential for NK cell differentiation in vitro and in vivo. However the molecular mechanisms by which IL-15 is able to drive NK differentiation remain poorly understood. Here we show that blocking interaction between the receptor tyrosine kinase Axl and its ligands (Gas6 and protein S) by either soluble Axl/immunoglobulin Fc fusion protein (Axl-Fc) or warfarin, a vitamin K inhibitor, diminished the number and percentage of CD3⁻CD56⁺ NK cells differentiated from CD34⁺ human hematopoietic progenitors (HPCs) in blood and secondary lymphoid tissues in the presence of IL-15. Axl-Fc or warfarin increased HPC apoptosis, reduced the frequency of NK precursors, and resulted in impaired IFN-γ production. Mechanistically, in human CD34⁺ HPCs, Axl-Fc significantly inhibited IL-15-induced signaling events, such as phosphorylation of STAT5 and ERK. Taken together, our results suggest that the Axl/Gas6 pathway is important for IL-15-induced differentiation of NK cells from human CD34⁺ HPCs.