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CMV Seropositive Children Show Inhibition of In Vitro EBV Infection that is Associated with CD8+CD57+ T-cell Enrichment and IFN-g
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Epstein-Barr virus (EBV), a human herpesvirus, is commonly acquired during childhood and persists latently in B cells. EBV seropositivity has been connected to immune modulatory effects such as altered T- and NK-cell functional responses as well as protection against early IgE-sensitization, but due to the asymptomatic presentation during childhood little is known regarding the infection process in children of different ages. Here, we used mononuclear cells from cord blood, 2-year and 5-year old EBV-naïve 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 relation to IFN-g 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 of older children. We also related results to serostatus to cytomegalovirus (CMV), a persistent herpesvirus that can affect differentiation status of T- and NK cells. As compared to 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-g  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 points to the ability of viruses with immune-modulatory functions, like CMV, to impact on immune responses within the host system.

Keyword [en]
Children, EBV, CMV, B cell, T cell, IFN-γ
National Category
Immunology
Research subject
Immunology
Identifiers
URN: urn:nbn:se:su:diva-93008OAI: oai:DiVA.org:su-93008DiVA: diva2:643716
Available from: 2013-08-28 Created: 2013-08-28 Last updated: 2013-08-30Bibliographically approved
In thesis
1. Immune maturation in early childhood and the influence of herpesvirus infections
Open this publication in new window or tab >>Immune maturation in early childhood and the influence of herpesvirus infections
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The quality of immune responses develops from birth into adulthood and in the context of the host microbial environment. The aim of this work was to study immune maturation during childhood, and how this process can be affected by the common herpesviruses; Epstein-Barr virus (EBV) and cytomegalovirus (CMV).

In paper I we studied monocytes, an important cell type for immunity in the newborn. We showed that the neonatal monocyte subsets exist in similar frequencies as adult subsets, and have a potent capacity for pro-inflammatory cytokine production. In paper II, III and IV we studied the effects of EBV and CMV infections on immune cell function in children. In paper II we found that monocyte-induced NK-cell production of IFN-γ, and plasma IFN-γ levels, were decreased in 2-year old EBV- and/or CMV-seropositive children and mostly so in co-infected children. In paper III we found that in 5-year old children, EBV and CMV co-infection was associated with the highest levels of differentiated NKG2C+ NK cells. CMV+ children had higher plasma IFN-γ and IL-15 levels and higher NK-cell cytotoxic capacity. In vitro PBMC systems showed elevated frequencies of NKG2C+ NK cells in the presence of EBV-infected cells. In paper IV we showed that a child’s age and subsequent capacity for anti-viral cytokine production affects in vitro EBV infection in terms of B-cell proliferation and B-cell acquisition of memory phenotype. PBMC from CMV+ children had lower EBV-induced accumulation of switched memory B cells, which was connected to high prevalence of CD57+CD8+ T cells and IFN-γ production.

Taken together, this thesis work shows that monocyte subsets at birth can give potent functional responses and that latency with EBV and CMV has a significant effect on the differentiation process and functional capacity of anti-viral effector cells during childhood. This in turn could affect responses to related or unrelated infections or even to non-invasive antigens such as allergens.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2013. 91 p.
Keyword
Immune differentiation, monocytes, NK cells, B cells, T cells, Epstein-Barr virus; EBV, cytomegalovirus; CMV, IFN-γ
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-93034 (URN)978-91-7447-745-0 (ISBN)
Public defence
2013-10-11, De Geersalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 10:00 (English)
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Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.

Available from: 2013-09-19 Created: 2013-08-29 Last updated: 2013-09-17Bibliographically approved

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