J Immunol. 2013 Dec 1;191(11):5669-76.

Cytomegalovirus-seropositive children show inhibition of in vitro EBV infection that is associated with CD8+CD57+ T cell enrichment and IFN-γ.

Sohlberg E, Saghafian-Hedengren S, Rasul E, Marchini G, Nilsson C, Klein E, Nagy N, Sverremark-Ekström E.

Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, 106 91 Stockholm, Sweden;

 

Abstract

EBV, a human herpesvirus, is commonly acquired during childhood and persists latently in B cells. EBV seropositivity has been connected to immunomodulatory effects such as altered T and NK cell functional responses as well as protection against early IgE sensitization; however, owing to the asymptomatic presentation during childhood little is known regarding the infection process in children of different ages. In this study, we used mononuclear cells from cord blood and from 2- and 5-y-old EBV-naive children for in vitro EBV infection. We show that the degree of EBV-induced B cell activation and expansion differs between age groups and in particular in relationship to IFN-γ production capacity. EBV infection induced redistribution between B cell subsets with enrichment of IgD(+)CD27(+) cells (commonly referred to as non-switched memory) in infected cord blood cell cultures, and of IgD(-)CD27(+) cells (switched memory) in cell cultures from older children. We also related results to serostatus to CMV, a persistent herpesvirus that can affect differentiation status of T and NK cells. As compared with CMV(-) children, the EBV-induced enrichment of IgD(-)CD27(+) B cells was significantly reduced in infected cell cultures from CMV(+) children. This effect was associated with high levels of IFN-γ and frequencies of highly mature CD8(+)CD57(+) T cells in CMV(+) children. Our results demonstrate that both a child’s age and serostatus to CMV will have an impact on EBV-induced B cell activation and expansion, and they point to the ability of viruses with immunomodulatory functions, such as CMV, to affect immune responses within the host system.

PMID: 24140645

 

SUPPLEMENT

After infection, both EBV and CMV establish latency and persist in immune cells. A significant proportion of memory cells then control these viruses, and although both viruses are connected to disease (1), they cause no or minor problems in healthy and immune competent hosts. In a series of studies, we have investigated how these viruses influence immune cells as well as IgE-sensitization during childhood in a birth cohort of Swedish children. We showed that these viruses, and in particular the time-point of primary EBV infection, modulate the risk of IgE-sensitization during childhood (2,3). Further, herpesvirus latency affects the frequencies of NK- and T-cell subsets and NK-cell responses in children, and co-infection with CMV and EBV differs from having either virus alone in terms of immune-modulation (4,5).

Although EBV is normally encountered in early childhood, knowledge regarding the immune response to EBV has largely originated from studies of infectious mononucleosis in teen-agers/adults, as clinical symptoms are seldom seen in infants. We show that both age and a positive serostatus to CMV, and thus enriched T- and NK-cell subsets with mature phenotype, alter the immune response to EBV. For example, upon in vitro infection with EBV the formation of switched memory B cells was more restricted in CMV-positive children compared to CMV-negative children. Our findings support that this partly was a result of a more pronounced activation of IFN-g producing T cells in the CMV-positive children. This suggests that immune maturity at a primary EBV infection, and whether other viruses with immune modulatory capacity are present in the host, will affect how the immune system is influenced by the EBV infection.

 

REFERENCE

  1. White DW, Beard RS, Barton ES. Immune modulation during latent herpesvirus infection. Immunol Rev 2011; 245: 189-208.
  2. Nilsson C, Linde A, Montgomery SM, Gustafsson L, Nasman P, Blomberg MT, Lilja G.Does early EBV infection protect against IgE sensitization? J Allergy Clin Immunol 2005; 116:438-44.
  3. Saghafian-Hedengren S, Sverremark-Ekström E, Lilja G, Linde A, Nilsson C. Early life EBV-infection protects against persistent IgE-sensitization. J Allergy Clin Immunol 2010; 125: 433-438
  4. Saghafian-Hedengren S, Sundström S, Sohlberg E, NilssonC, Troye-BlombergM, Berg L, Sverremark-Ekström E. Herpes virus seropositivity in childhood associates with decreased monocyte-induced NK-cell IFN-g production. J Immunol 2009; 182: 2511-2517.
  5. Saghafian-Hedengren S, Sohlberg S, Theorell J, Carvalho-Queiroz C, Nagy N, Nilsson C, Bryceson Y, Sverremark-Ekström E. Epstein-Barr virus co-infection in children boosts cytomegalovirus-related differentiation of Natural Killer cells. J Virol 2013; 87: 13446-55.
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