In Search of Adaptive-Like Features of NK Cells Co-Expressing NKG2C and NKG2A

Adaptive-like functions of NK cells have been extensively studied in the context of human cytomegalovirus (HCMV) infection, particularly for NKG2C⁺ NK cells. The NKG2A inhibitory and the NKG2C activating receptors share a common ligand, the HLA-E molecule, and can be co-expressed in a unique NK cell subset. However, key characteristics and memory response capacity of this subset remain unclear. We analyzed the proliferative responses, functional attributes and transcriptional signatures of NKG2C⁺NKG2A⁺ subsets within CD57⁺ and CD57^- fractions of peripheral blood CD56^dimNK cells by comparing them with NKG2A^- counterparts. Double-positive NK cells displayed a less mature phenotype, increased MHC-II and exhibited transcriptome profile indicating enhanced adhesion/migration capacities with no difference in adaptive state associated genes expression. These cells showed enhanced proliferation compared to NKG2A^- cells, which was not reduced upon interaction with HLA-E presenting the HCMV (VMAPRTLFL, LFL) peptide. CD57⁺NKG2C⁺NKG2A⁺ subset showed enhanced antibody-dependent IFNγ production. Expanded upon LFL stimulation this subset again exhibited enhanced IFNγ production capacity along with peptide-specific mRNA expression profile, demonstrating an adaptive-like response. These results provide additional insight into the diversity of HCMV-specific NK cell subsets, highlighting NKG2A⁺NKG2C⁺ NK cells' immunotherapeutical potential.