Abstract
NK cells contribute to postvaccination immune responses after activation by IL-2 from Ag-specific memory T cells or by cross-linking of the low-affinity IgG receptor, CD16, by Ag–Ab immune complexes. Sensitivity of NK cells to these signals from the adaptive immune system is heterogeneous and influenced by their stage of differentiation. CD56dimCD57+ NK cells are less responsive to IL-2 and produce less IFN-γ in response to T cell–mediated activation than do CD56bright or CD56dimCD57− NK cells. Conversely, NK cell cytotoxicity, as measured by degranulation, is maintained across the CD56dim subsets. Human CMV (HCMV), a highly prevalent herpes virus causing lifelong, usually latent, infections, drives the expansion of the CD56dimCD57+NKG2C+ NK cell population, skewing the NK cell repertoire in favor of cytotoxic responses at the expense of cytokine-driven responses. We hypothesized, therefore, that HCMV seropositivity would be associated with altered NK cell responses to vaccine Ags. In a cross-sectional study of 152 U.K. adults, with HCMV seroprevalence rate of 36%, we find that HCMV seropositivity is associated with lower NK cell IFN-γ production and degranulation after in vitro restimulation with pertussis or H1N1 influenza vaccine Ags. Higher expression of CD57/NKG2C and lower expression of IL-18Rα on NK cells from HCMV seropositive subjects do not fully explain these impaired responses, which are likely the result of multiple receptor–ligand interactions. This study demonstrates for the first time, to our knowledge, that HCMV serostatus influences NK cell contributions to adaptive immunity and raises important questions regarding the impact of HCMV infection on vaccine efficacy.
Highlights
We demonstrate for the first time, to our knowledge, that the contribution of NK cells to adaptive immune responses is affected by Human CMV (HCMV) infection: NK cells from HCMV+ donors respond significantly less well than cells from HCMV2 donors to killed whole-cell pertussis or inactivated whole H1N1 influenza virus
Our data demonstrate for the first time, to our knowledge, that there is an additive effect between the cytokine and the IgG pathways driving NK cell IFN-g production, because both IgG depletion and IL-2 blockade reduced NK cell IFN-g responses in response to stimulation of PBMCs with pertussis vaccine
We propose that CD16 crosslinking by immune complexes upregulates CD25 expression, increasing sensitivity to T cell–derived IL-2, and thereby enhancing IFN-g production
Summary
NK cell CD25+, CD25+IFN-g+, and CD107a+ expression in response to HCC (high concentrations of IL-12 and IL-18) were all significantly higher in HCMV2 compared with HCMV+ donors (Fig. 2A–C). NK cell responses did not differ significantly between males and females, there was a trend for median responses to be higher in women than in men, and this reached statistical significance (p , 0.05) for the IFN-g response to pertussis + LCC in HCMV+ donors (data not shown).
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