Relationship of NKG2C Copy Number with the Distribution of Distinct Cytomegalovirus-Induced Adaptive NK Cell Subsets

CD94/NKG2C and lack of FcRg (FcRg) expression are considered markers of the adaptive NK cell response to human CMV (HCMV) infection. Despite the fact that FcRg2 and NKG2Cbright NK cells share some phenotypic, epigenetic, and functional features, their relationship remains unclear. To address this issue, a systematic analysis of NKG2Cbright and FcRg expression was carried out in NK cells from a cohort of healthy young adults (n = 81) considering NKG2C copy number, previously related to the magnitude of NKG2C+ NK cell expansion. NKG2Cbright and FcRg2 NK cells coincided in a subgroup of HCMV+ individuals, pointing to a common host-virus interaction pattern. Even though FcRg loss was often confined to expanded NKG2Cbright NK cells, both markers appeared occasionally dissociated, consistent with the existence of distinct adaptive NK cell subsets. Remarkably, FcRg loss was mostly accumulated within the NKG2Cbright subset in NKG2C+/+ subjects, whereas NKG2C2FcRg2 NK cell subpopulations were more frequently detected in NKG2C+/del donors and also in NKG2Cdel/del individuals, independently of activating killer Ig-like receptor expression. The distribution of other NK receptors (i.e., killer Ig-like receptor, LILRB1, or CD57) supported a sequential differentiation from NKG2CbrightFcRg+ to NKG2CbrightFcRg2 NK cells. Noticeably, NKG2Cbright NK cells produced more TNF-α in response to Ab-dependent activation, regardless of their FcRg levels. Moreover, the TNF-α response of NKG2C2FcRg2 subpopulations was lower than that of concurrent NKG2CbrightFcRg2 NK cells, further supporting that FcRg levels and enhanced potential for cytokine production are uncoupled. Overall, our data extend the characterization of adaptive NK cell subsets that differentiate in response to HCMV, supporting a relationship between their distribution and NKG2C copy number.