Schematic diagram of human NK cell development.

NK cell progenitors that respond to early-acting RTK ligands (FL and KL) differentiate into IL-15–responsive NK cell precursors by up-regulating the IL-15R complex on their surface. The NK precursors then respond to IL-15 to differentiate into mature NK cells. Characterization of the resultant CD56^bright NK cells produced strongly suggests that other (eg, stromal) signals are likely required for complete NK cell differentiation. FL^−/− mice are deficient in NK cells, suggesting that this RTK ligand serves a critical, nonredundant function in NK cell development or expansion in mice in vivo, most likely at the level of the NK cell progenitor.285 In addition, RAG2/γ_c^−/− mice (lacking T, B, and NK cells) reconstituted with c-kit^−/− progenitors have defects in NK cell expansion and survival, suggesting that KL serves a critical role in these functions in vivo.286 Further, IL-15Rα^−/− and IL-15^−/− mice lack NK cells, suggesting that IL-15 is critical for the differentiation of mature NK cells from NK cell precursors (Table 1).