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Inhibitory KIRs play a central role in regulating NK cell activity. KIR2DL2/3 bind to HLA-C molecules, but the modulation of these interactions by viral infections and presentation of viral epitopes is not well-understood. We investigated whether the frequencies of KIR2DL2/3 +  NK cells recognizing HLA-C * 03:04/viral peptide complexes were impacted by YFV vaccination or HIV-1 and HCV infection.  Ex vivo  HLA class I tetramer staining of primary human NK cells derived from YFV-vaccinated individuals, or HIV-1- or HCV-infected individuals revealed that the YFV/HLA-C * 03:04-NS2A 4−13 -tetramer bound to a larger proportion of KIR2DL2/3 +  NK cells compared to HIV-1/HLA-C * 03:04-Gag 296−304 - or HCV/HLA-C * 03:04-Core 136−144 -tetramers. The YFV/HLA-C * 03:04-NS2A 4−13 -tetramer also exhibited a stronger avidity to KIR2DL2/3 compared to the other tested tetramers. The proportional frequencies of KIR2DL2/3 +  NK cells binding to the three tested HLA-C * 03:04 tetramers were identical between YFV-vaccinated individuals or HIV-1- or HCV-infected individuals, and remained stable following YFV vaccination. These data demonstrate consistent hierarchies in the frequency of primary KIR2DL2/3 +  NK cells binding HLA-C * 03:04/peptide complexes that were determined by the HLA-C-presented peptide and not modulated by the underlying viral infection or vaccination.

Stable Frequencies of HLA-C*03:04/Peptide-Binding KIR2DL2/3+ Natural Killer Cells Following Vaccination