Programmed differentiated natural killer cells kill leukemia cells by engaging SLAM family receptors

Natural killer (NK) cells are important innate immune cells that can directly kill transformed or virus-infected cells. The adoptive transfer of NK cells has been used to treat hematological malignancies; however, the limited sources and quantities of NK cells have restricted their clinical application. Here, we acquired sufficient quantities of functional NK cells from CD34(+) cells treated with a cytokine cocktail. Microarray analysis of the cultured cells revealed a two-stage pattern of programmed differentiation during NK cell development. Different transcription factors were enriched during these two stages, suggesting that preparation of progenitors committed to the NK cell lineage occurs in program 1, while NK cell transformation and maturation occur in program 2. Cultured NK cells highly expressed signaling lymphocytic activation molecule (SLAM) family receptors (SFRs), while leukemia cells expressed SFR ligands. The engagement of these SFRs strengthened the cytotoxicity of NK cells toward leukemia cells. These results demonstrate a simple method of obtaining sufficient NK cells for clinical application, and have categorized NK cell differentiation according to commitment and transformation programs. Moreover, the binding between SFRs on NK cells and their ligands on leukemia cells suggests a new basis for NK cell therapy for treatment of leukemia.