FcRγ− NK cell induction by specific CMV and expansion by subclinical viral infections in rhesus macaques

Long-lived ‘memory-like’ NK cells, characterized by FcRγ-deficiency and enhanced responsiveness to antibody-bound virus-infected cells, have been found in certain human cytomegalovirus (HCMV)-seropositive individuals. Because humans are exposed to numerous microbes and environmental agents, specific relationships between HCMV and FcRγ-deficient NK cells (also known as g-NK cells) have been challenging to define. Here, we show that a subgroup of rhesus cytomegalovirus (RhCMV)-seropositive macaques possesses FcRγ-deficient NK cells that stably persist and display phenotype resembling human FcRγ-deficient NK cells. Moreover, these macaque NK cells resembled human FcRγ-deficient NK cells with respect to functional characteristics, including enhanced responsiveness to RhCMV-infected target in an antibody-dependent manner and hypo-responsiveness to tumor and cytokine stimulation. These cells were not detected in specific-pathogen-free (SPF) macaques free of RhCMV and six other viruses; however, experimental infection of SPF animals with RhCMV strain UCD59, but not RhCMV strain 68-1 or SIV, led to induction of FcRγ-deficient NK cells. In non-SPF macaques, co-infection by RhCMV with other common viruses was associated with higher frequencies of FcRγ-deficient NK cells. These results support a causal role for specific cytomegalovirus strain(s) in the induction of FcRγ-deficient NK cells, and suggest that co-infection by other viruses further expands this memory-like NK cell pool. ### Competing Interest Statement The authors have declared no competing interest.