Polygenic polymorphisms cooperate to drive expansion of HCMV adaptive NK cell and NK-like T cell populations

Human cytomegalovirus (HCMV) infection drives the expansion of several innate and innate-like lymphocyte populations. Characterized by high cell surface expression of NKG2C, these populations include the adaptive CD56+ FcϵRIγ- NK cell, an NK-like TCRαβ+CD8+ T cell population and a Vγ9/Vδ1+ T cells. Beyond NKG2C expression, both the adaptive NK cell and the NK-like T cell population exhibit enhanced cytokine response to antibody-dependent cellular cytotoxicity (ADCC). Expansion of each population is only observed in 30-40% of HCMV+ individuals and is independent of expansion of each other. In this study, we evaluated 200 healthy donors and identified several immunogenetic factors that influence NKG2C expression across the three lymphocyte populations. NKG2C (KLRC2) copy number and allelic polymorphism was associated with NKG2C+ NK cell frequency and surface expression density in HCMV- but not in HCMV+ individuals. Investigating other genetic loci encoding proteins related to adaptive NK function, we found that CD16a and HLA-E alleles act cumulatively with NKG2C copy number to drive NKG2C expression on lymphocytes among HCMV+ individuals. Polymorphism of the NKG2C ligand HLA-E influences strength of NK cell activation via NKG2C, where NK responsiveness was lower in individuals with the HLA-E*01:03 genotype, while CD16a polymorphism influenced strength of ADCC response among NKG2C+ TCRαβ+CD8+ T cells. Based on these observations, we conclude that genetic polymorphisms in NKG2C, CD16a and HLA-E shape the NKG2C+ repertoire, influence NKG2C-mediated NK function and dictate capacity of ADCC in response to HCMV infection. Immunogenetic polymorphism among NKG2C-related genes therefore tunes innate immunity to HCMV infection providing additional protection beyond adaptive immunity.