Recipient expression of ligands for donor inhibitory KIRs enhances NK-cell function to control leukemic relapse after haploidentical transplantation.

Natural killer (NK) cells that express self-HLA-specific receptors (where HLA is human leukocyte antigen) are "licensed" and more readily activated than unlicensed cells; therefore, NK-cell licensing could influence the antileukemia effects of NK cells following haploidentical stem cell transplantation (haplo-SCT). In this study, we compared the functionality of reconstituting NK cells, based on CD107α expression and interferon-γsecretion, in a cohort of 29 patients that expressed (n = 8) or lacked (n = 21) class I human leukocyte antigens for donor inhibitory killer cell immunoglobulin-like receptors (KIRs) following T-cell-replete haplo-SCT. We also addressed whether recipient expression of class I ligands for donor inhibitory KIRs could predict relapse occurrence in another cohort of 188 patients. A longitudinal analysis indicated that patients presenting class I for all donor inhibitory KIRs showed more capable functional NK effector cells when tested against class I negative K562 cells and primary leukemic cells within 3 months of transplantation. The lowest 7-year relapse incidence was observed when donor KIRs were ligated by recipient class I (n = 60) compared with donor-host partnerships where donor KIR(+) cells were ligated by donor, but not recipient class I (n = 86, p = 0.026) or KIRs that were ligated by neither donor nor recipient class I (n = 42, p = 0.043). This study suggests that haplo-SCT recipients presenting class I for donor inhibitory KIRs promote NK-cell licensing, leading to decreased relapse rates.