Herpesvirus Seropositivity in Childhood Associates with Decreased Monocyte-Induced NK Cell IFN-γ Production

Abstract

EBV infection is inversely associated with IgE sensitization in children, and this association is further enhanced by CMV coinfection. In mice, herpesvirus latency causes systemic innate activation and protection from bacterial coinfection, implying the importance of herpesviruses in skewing immune responses during latent infection. Early control of viral infections depends on IFN-γ release by NK cells, which generally requires the presence of accessory cells. We investigated IFN-γ production by NK cells in PBMCs from children seropositive (SP) for EBV alone, for both EBV and CMV, or seronegative for both viruses. The ability of classical (CD14++CD16−) and proinflammatory (CD14+CD16+) monocytes to induce autologous NK cell IFN-γ was studied by coculture experiments with enriched CD3−CD56+ cells. Transwell experiments were used to evaluate how monocytes interact with NK cells to induce IFN-γ synthesis. SP children had a significantly reduced proportion of IFN-γ+ NK cells and cognate intracellular IFN-γ levels, which was more pronounced in CMV-coinfected subjects. Also, resting PBMCs of SP children displayed lower proportions of proinflammatory monocytes. IFN-γ production by NK cells was dependent on interactions with monocytes, with the proinflammatory subset inducing the highest IFN-γ. Finally, SP children had markedly lower levels of plasma IFN-γ, concurrent with in vitro findings. Herpesvirus infections could be one contributing factor for maturation toward balanced Th1-Th2 responses. Our data indicate that early infection by herpesviruses may affect NK cell and monocyte interactions and thereby also influence the development of allergies.

Cytomegalovirus-Seropositive Children Show Inhibition of In Vitro EBV Infection That Is Associated with CD8+CD57+ T Cell Enrichment and IFN-γ

“…Owing to the asymptomatic presentation of EBV during infancy, little is known regarding the course of infection in children of different ages. Our previous studies indicated that the time point of EBV acquisition during early childhood, and the occurrence of coinfection with CMV, might affect immunomodulation by the virus (4,29). In this study, we show in an in vitro-based infection system that a child's age and serostatus to CMV, and subsequent ability to mount IFN-g responses, affect EBV-induced activation and expansion of B cells.…”

“…Our group has found that latency with EBV and CMV influenced functional responses of T and NK cells and that these responses differed in children coinfected with both viruses compared with those with EBV alone (29,30). Furthermore, the time point of primary EBV infection during early childhood appeared important for EBV-induced modulation of immune responses (4).…”

Epstein-Barr Virus Coinfection in Children Boosts Cytomegalovirus-Induced Differentiation of Natural Killer Cells

“…To our knowledge, however, no studies have yet focused on the possible synergistic role of EBV and CMV coinfection on antiviral effector cell maturation. Notably, earlier studies from our group have suggested a synergistic protective effect of EBV and CMV coinfection against IgE sensitization (24), and distinct modulation of NK cell gamma interferon (IFN-␥) production capacity by the two viruses (25). This raises the intriguing possibility of in vivo interplay of CMV and EBV latency and that this interplay may have a functional imprint on subsequent immune responses early in life.…”

“…To understand whether herpesvirus carriage also associated with priming the NK cell function in humans, we induced NK cell activation through different pathways in PBMC from a group of children. We used K562 and Daudi target cells to induce activation via NK cell receptors, anti-CD16 antibodies to induce antibodydependent cell-mediated cytotoxicity, and the addition of peptidoglycan (a Toll-like receptor 2 agonist), together with IL-15, to mimic accessory cell-mediated NK cell activation (25).…”

Rapid NK cell differentiation in a population with near-universal human cytomegalovirus infection is attenuated by NKG2C deletions

“…Although some of this is heterogeneity may be genetically determined and/or stochastic, 37 exposure to infections in addition to HCMV may also affect NK cell maturation. 7,15,17,56 Further studies are needed to determine whether this is simply a cytokine-driven expansion, and thus likely to occur in response to many acute inflammatory stimuli, or whether some pathogens express specific ligands for CD57…”