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Production1
* Department of Immunology, Wenner-Gren Institute, Stockholm University, Stockholm, Sweden;
Department of Clinical Science and Education, Sodersjukhuset, Karolinska Institutet and Sachs’ Children's Hospital, Stockholm, Sweden;
Department of Epidemiology, Swedish Institute for Infectious Disease Control, Solna, Sweden; and
Department of Microbiology, Tumour and Cell Biology, Strategic Research Center Integrative Recognition in the Immune System, Karolinska Institutet, Stockholm, Sweden
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-
release by NK cells, which generally requires the presence of accessory cells. We investigated IFN- 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- 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- synthesis. SP children had a significantly reduced proportion of IFN-+ NK cells and cognate intracellular IFN- levels, which was more pronounced in CMV-coinfected subjects. Also, resting PBMCs of SP children displayed lower proportions of proinflammatory monocytes. IFN- production by NK cells was dependent on interactions with monocytes, with the proinflammatory subset inducing the highest IFN-. Finally, SP children had markedly lower levels of plasma IFN-, 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Swedish Research Council Grants 74X-15160-03-2, 57X-15160-05-2, and K2006-74X-15139-03-02); European Union Grants LSHP-CT 2004 and 503578; the Vardal Foundation; the Swedish Asthma and Allergy Association’s Research Foundation; the Swedish Medical Society; and the Golden Jubilee Memorial, Crown-Princess Lovisa and Axel Tielman, Golje, Hesselman, Åhlén, and Apotekare Hedberg foundations.
2 Address correspondence and reprint requests to Dr. Shanie Saghafian-Hedengren, Stockholm University, Department of Immunology, Svante Arrheniusväg 16-18, 106 91 Stockholm, Sweden. E-mail address: shanie{at}imun.su.se
5 Abbreviations used in this paper: DC, dendritic cell; PGN, peptidoglycan; SN, seronegative; SP, seropositive; GeoMFI, geometrical mean fluorescence intensity.
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