Possible constellations of NK cell alloreactivity are depicted. (A) Licensed donor NK cells (ie, NK cells that have iKIRs for self–HLA class I) are inhibited via engagement of the iKIR by the recipients’ ligands (HLA class I), which exert a strong inhibitory signal; thus, these donor NK cells cannot lyse recipients’ leukemic blasts (NK cell nonalloreactivity). (B) iKIRs of licensed NK cells are not engaged by the KIRLs, and the donor NK cells are activated and lyse recipients’ leukemic blasts (NK cell alloreactivity). (C) Recipients’ blasts lack HLA class I expression and, therefore, cannot inhibit donor NK cells, resulting in activation of donor NK cells. (D) NK cells do not express KIRs and, therefore, have not been licensed. KIR-negative NK cells are one of the earliest lymphocyte populations that reconstitute after T cell–depleted HSCT. These NK cells are hyporesponsive but might become responsive upon cytokine stimulation.