EBV Infection Alters NK Cell Phenotype Distinctly From hCMV

ABSTRACT Natural killer (NK) cells are vital in the antiviral response regulated by inhibitory and activating receptors, including NKG2 and KIR families, which bind HLA‐I. While the adaptive features of NK cells in response to human cytomegalovirus (hCMV) have been well described, their behavior during Epstein‐Barr virus (EBV) infection and the influence of KIR‐HLA combinations in healthy carriers of these viruses remains unclear. We performed high‐resolution HLA genotyping, phenotypic profiling of NK cell subsets, and serological testing for hCMV and EBV‐specific IgG in 85 healthy adult donors. hCMV‐seropositive individuals exhibited significant expansions of NKG2C + and HLA‐DR + NK cell subsets, with the proportion of NKG2C + cells strongly correlating with hCMV‐IgG titers. In contrast, EBV infection was associated with increased frequencies of terminally differentiated CD56 dim , NKG2A – , CD57+ NK cells and elevated expression of inhibitory KIRs, but not NKG2C or HLA‐DR. EBV‐IgG titers correlated with CD57 and KIR2DS4 levels. Among KIR2DS4‐expressing donors, carriage of at least one HLA‐C2 allele was associated with elevated EBV‐IgGs. The precise analysis of KIR2DL2/DL3, KIR2DS4, and KIR2DL1 revealed dependencies on EBV‐IgG titers, with no associations with hCMV. These findings highlight the differential impacts of hCMV and EBV on NK cells and underscore the relevance of HLA‐KIR landscapes in shaping antiviral immunity.