BACKGROUND

Natural Killer (NK) cells are members of the innate lymphoid cell (ILC) family (1) and provide immediate immune responses against transformed and virally infected cells (2). Although NK cells are classically regarded as part of the innate immune system, accumulating evidence indicates that NK cells can mediate immunological memory and display adaptive features, specifically in response to viral infections (3, 4). The contribution of human NK-cell responses to the defense against viral infections is highlighted by rare cases of patients with genetic NK-cell deficiencies, who suffer from severe and disseminated infections, especially caused by herpesviruses such as human cytomegalovirus (HCMV)(5). In contrast to virus-specific CD8+ or CD4+ T cells, adaptations of the NK-cell compartment to HCMV are not detected in all, but only in 30–40% of HCMV-seropositive healthy individuals (6, 7). In these individuals, the activating receptor NKG2C (CD159c) as well as activating killer cell immunoglobulin-like receptors (KIR) mark a subset of NK cells, which has adapted to HCMV (6, 8) and has, therefore, previously been termed “adaptive NK cells”(9). Several peculiar features of adaptive NK cells such as epigenetic alterations (9, 10) and functional properties (11) have been defined, while many other aspects remain incompletely understood or unexplored. To further investigate adaptive NK cells and address open questions, it is essential to definitively discriminate between adaptive NKG2C+ NK cells, which were generated by HCMV infection in a sub-group of HCMV-seropositive individuals, and conventional NKG2C+ NK cells, which are present at low frequencies at steady state even in HCMV-seronegative individuals. Since the proportion of NKG2C+ NK cells in HCMV-seropositive donors varies considerably (6, 8, 11), the frequency of NKG2C-expressing CD56dim NK cells is not a sufficient criterion to identify adaptive NKG2C+ NK cells, although setting thresholds has been previously proposed (12). Consequently, assessing other attributes is required to reliably detect adaptive NK cells in HCMV-seropositive individuals. Preferential expression of self-HLA class I-binding inhibitory KIR is a hallmark of adaptive NK cells (6, 8, 11). Hence, identification of adaptive NK-cell subsets as