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Epstein-Barr Virus Co-infection in Children Boosts Cytomegalovirus-induced Differentiation of Natural Killer Cells
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
Visa övriga samt affilieringar
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

During childhood, infections with cytomegalovirus (CMV) and Epstein-Barr virus (EBV) can occur in close temporal proximity. Active as well as latent CMV infection is associated with enlarged subsets of differentiated NK- and cytotoxic T cells. How EBV infection may influence CMV-driven immune differentiation is not known. Here we found that EBV co-infection selectively influenced the NK-cell compartment of CMV-seropositive (CMV+) children. Co-infected children had significantly higher proportions of peripheral-blood NKG2C+ NK cells than CMV+EBV children. Ex vivo NK-cell degranulation after target cell stimulation and plasma IL-15 levels were significantly higher in CMV+ children. EBV co-infection related with the highest levels of plasma IL-15 and IL-12p70. Remarkably, in vitro EBV infection of peripheral blood mononuclear cells (PBMC) from EBVCMV+ children increased NKG2C+ NK-cell proportions. A similar tendency was seen in co-cultures of PBMC with EBV+ lymphoblastoid B-cell lines (LCL) and IL-15. Following K562 challenge, NKG2C+ NK cells excelled in regards to degranulation and production of IFN-g, regardless of previous co-culture with LCL. Taken together, our data suggest that herpesvirus interplay during childhood could contribute to an in vivo environment supporting differentiation and maintenance of distinct NK-cell populations. This viral imprint may affect subsequent immune responses through altered distributions of effector cells.

Nyckelord [en]
CMV, EBV, co-infection, NK cell, NKG2C
Nationell ämneskategori
Immunologi
Forskningsämne
immunologi
Identifikatorer
URN: urn:nbn:se:su:diva-93007OAI: oai:DiVA.org:su-93007DiVA, id: diva2:643713
Tillgänglig från: 2013-08-28 Skapad: 2013-08-28 Senast uppdaterad: 2013-08-30Bibliografiskt granskad
Ingår i avhandling
1. Immune maturation in early childhood and the influence of herpesvirus infections
Öppna denna publikation i ny flik eller fönster >>Immune maturation in early childhood and the influence of herpesvirus infections
2013 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2013. s. 91
Nyckelord
Immune differentiation, monocytes, NK cells, B cells, T cells, Epstein-Barr virus; EBV, cytomegalovirus; CMV, IFN-γ
Nationell ämneskategori
Immunologi
Forskningsämne
immunologi
Identifikatorer
urn:nbn:se:su:diva-93034 (URN)978-91-7447-745-0 (ISBN)
Disputation
2013-10-11, De Geersalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Anmärkning

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

Tillgänglig från: 2013-09-19 Skapad: 2013-08-29 Senast uppdaterad: 2013-09-17Bibliografiskt granskad

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Sohlberg, EbbaSverremark-Ekström, Eva
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Institutionen för molekylär biovetenskap, Wenner-Grens institut
Immunologi

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