IMMUNOBIOLOGY

are essential effector molecules for natu-ral killer (NK)–cell cytotoxicity, but how Prf1 and GzmB expression is regulated during arming of NK cells is poorly de-fined. We show that human microRNA (miR)–27a * is a negative regulator of NK-cell cytotoxicity by silencing Prf1 and GzmB expression. Human miR-27a * spe-cifically bound to the 3 untranslated re-gions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells, and it functioned as a fine-tuner for homeostasis of the net amount of the effector proteins. Consistent with miR-27a * having an inhibitory role, knock-down of miR-27a * in NK cells dramatically increased cytotoxicity in vitro and de-creased tumor growth in a human tumor xenograft model. Thus, NK-cell cytotoxic-ity is regulated, in part, by microRNA, and modulating endogenous miR-27a * levels in NK cells represents a potential immuno-therapeutic strategy. (Blood. 2011;118(20): 5476-5486