The impact of cytomegalovirus infection on natural killer cell responses to vaccines

Vaccines are one of the most effective public health interventions, but factors influencing vaccine efficacy remain poorly understood. Natural killer (NK) cells contribute to adaptive immune responses following activation by IL-2 from memory T cells or crosslinking of CD16 by antigen-antibody complexes. Human cytomegalovirus (HCMV), a highly prevalent herpes virus, drives expansion of a mature CD56dimCD57+NKG2C+ NK cell subset, skewing the NK cell repertoire towards contact-dependent activation at the expense of cytokine sensitivity. I hypothesised that HCMV seropositivity would be associated with diminished NK cell activation during recall responses to vaccine antigens. To test this hypothesis, I first confirmed my ability to detect NK cell responses following restimulation with vaccine antigens and described differential activation by CD57-defined NK cell subsets: mature CD56dimCD57+ NK cells produced less IFN-γ than CD56bright or CD56dimCD57- NK cells, consistent with their reduced responsiveness to IL-2. Next, in a crosssectional study of 152 UK adults (36% HCMV+), I found that NK cell IFN-γ and degranulation responses to pertussis or H1N1 influenza vaccines were lower among HCMV+ individuals as compared to HCMV- individuals. The higher proportion of CD56dimCD57+NKG2C+ NK cells in HCMV+ individuals did not fully explain these impaired responses, as cells from all CD57/NKG2C-defined subsets responded less well. Finally, as I had detected lower expression of IL-18Rα on NK cells in HCMV+ individuals, I characterised pro-inflammatory cytokine interactions driving early NK cell activation and identified a central role for IL-18, due to its ability to synergise with IgG-CD16 crosslinking and common γ chain cytokines, including IL-2. This work demonstrates, for the first time, that HCMV serostatus influences heterogeneity in NK cell contributions to adaptive immunity and raises important questions regarding the impact of HCMV infection on vaccine efficacy. Furthermore, my work highlights that HCMV infection status is a major confounder of any study of human NK cell phenotype or function.