Impact of the Variable Killer Ig-Like Receptor–Human Leukocyte Antigen Interactions on Natural Killer Cell Cytotoxicity Toward Foreign CD4 T Cells

BACKGROUND: Natural killer (NK) cells are known to mount a response against foreign target cells, where the absence of the dominant inhibitory killer Ig-like receptor (KIR)–human leukocyte antigen (HLA) interaction immensely lowers the threshold for NK cell activation. NK cells could thus constitute a vital part in the mucosal defense against cell-associated sexually transmitted diseases. Here, we performed a detailed analysis of hitherto unexplored KIR–HLA-incompatible NK cell interactions. METHODS AND FINDINGS: In vitro, healthy NK cells were cocultured with CD4+ T cells derived from human immunodeficiency virus-1 patients, and the KIR-specific NK cell cytotoxicity was measured using flow cytometry. Genotyping of KIR and HLA predicted the KIR–HLA interactions occurring during these 124 allogeneic encounters. KIR2DL1+ NK cells were seen as the strongest intrinsic responders in the absence of their ligand with a 3.2-fold increase in KIR2DL1+ NK cells in the total NK cell response. An association between the size of the alloreactive NK cell population and the amount of CD4+ T cell death (p = 0.0023) and NK cell degranulation (p = 0.0036) was only present in NK cell donors with an activating KIR haplotype. CONCLUSION: We demonstrate differences in the activating effect of KIR–HLA incompatibility according to the KIR involved, with KIR2DL1 as the strongest responder. An activating KIR haplotype optimized the contribution of KIR–HLA-incompatible NK cells in the total NK cell response.