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Evidence from the RV144 HIV-1 vaccine trial implicates anti-HIV-1 antibody-dependent cellular cytotoxicity (ADCC) in vaccine-conferred protection from infection. Amongst effector cells that mediate ADCC are natural killer (NK) cells. The ability of NK cells to be activated in an antibody-dependent manner is reliant upon several factors. In general, NK cell mediated antibody-dependent activation is most robust in terminally differentiated CD57+ NK cells, as well as NK cells educated through ontological interactions between inhibitory killer immunoglobulin-like receptors (KIR) and their major histocompatibility complex class I (MHC-I or HLA-I) ligands. With regards to anti-HIV-1 antibody-dependent NK cell activation, previous research has demonstrated that the epidemiologically relevant KIR3DL1/HLA-Bw4 receptor/ligand combination confers enhanced activation potential. In the present study we assessed the ability of the KIR2DL1/HLA-C2 receptor/ligand combination to confer enhanced activation upon direct stimulation with HLA-I-devoid target cells or antibody-dependent stimulation with HIV-1 gp140-pulsed CEM.NKr-CCR5 target cells in the presence of an anti-HIV-1 antibody source. Amongst donors carrying the HLA-C2 ligand for KIR2DL1, higher IFNgamma production was observed within KIR2DL1+ NK cells than in KIR2DL1- NK cells upon both direct and antibody-dependent stimulation. No differences in KIR2DL1+ and KIR2DL1- NK cell activation were observed in HLA-C1 homozygous donors. Additionally, higher activation in KIR2DL1+ than KIR2DL1- NK cells from HLA-C2 carrying donors was observed within less differentiated CD57- NK cells, demonstrating observed differences were due to education and not an overabundance of KIR2DL1+ NK cells within differentiated CD57+ NK cells. These observations are relevant for understanding the regulation of anti-HIV-1 antibody-dependent NK cell responses. This article is protected by copyright. All rights reserved.
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