Adaptive NKG2C⁺ NK cells in cytomegalovirus seropositive individuals predominantly lack NKR‐P1A receptor expression

The impact of cytomegalovirus (CMV) infection in shaping natural killer (NK) cell receptor (NKR) repertoire highlights the importance of NKRs in immunity against CMV. NKR-P1A (CD161) is an inhibitory NKR, whose expression is lost during CMV infection, but its role in NK cell responses during CMV infection is not known. Here, we show selective expansion of adaptive NKG2C⁺ NK cells lacking NKR-P1A receptor (NKR-P1A^‒) due to their increased activation and proliferation compared with NKR-P1A⁺ NK cells in CMV-infected individuals. In vitro stimulation of PBMCs showed similar inherent proliferative capacity in both NKR-P1A⁺ versus NKR-P1A^‒ NK cells in steady state and upregulation, but not loss of NKR-P1A receptor expression, in sorted NK cells. Furthermore, CMV infection induced differential gene expression profiles in NKR-P1A⁺ versus NKR-P1A^‒ NK cells, and only NKR-P1A^‒ NK cells exhibited transcriptome signatures associated with adaptive NK cells in CMV-infected individuals. This study further highlights the impact of CMV infection in shaping NK cell receptor repertoire and exclusion of NK cells that express the NKR-P1A receptor from the adaptive NKG2C⁺ NK cell population that expands during CMV infection.