Human Cytomegalovirus Infection Increases Both Antibody- and Non–Antibody-Dependent Cellular Reactivity by Natural Killer Cells

BACKGROUND: Antibody-mediated rejection in solid organ transplantation is an important immunological barrier to successful long-term graft survival. Next to complement activation, natural killer (NK) cells have been implicated in the process. Human cytomegalovirus (CMV), independently associated with decreased graft survival, has a strong imprint on the immune response. Here, we assessed the effect of CMV status on alloreactive NK cell reactivity. METHODS: We compared antibody-mediated NK cell cytolytic activity (CD107a expression) and IFNγ production between healthy CMV-seropositive (n = 8) and CMV-seronegative (n = 11) individuals, in cocultures of NK cells with anti-HLA class I or rituximab (control) antibody-coated Raji cells. RESULTS: First, we showed that within the NKG2C+ NK cells, it is specifically the NKG2C+/A− subset that is enriched in CMV+ individuals. We then observed that in particular the NK cell antibody-dependent cell mediated cytotoxicity (ADCC), but also non-ADCC alloreactivity toward HLA-positive target cells was increased in CMV+ individuals as compared to CMV− ones. This enhanced ADCC as well as non-ADCC NK cell reactivity in CMV+ individuals was particularly characterized by a significantly higher number of ILT2+ and NKG2C+ NK cells that possessed cytolytic activity and/or produced IFNγ in response to HLA-positive target cells. CONCLUSIONS: With regard to organ transplantation, these data suggest that CMV infection enhances NK cell alloreactivity, which may pose an additional adverse effect on graft survival, especially in the presence of donor specific antibodies.