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Immune maturation in early childhood and the influence of herpesvirus infections
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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 [en]
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: urn:nbn:se:su:diva-93034ISBN: 978-91-7447-745-0 (print)OAI: oai:DiVA.org:su-93034DiVA: diva2:644082
Public defence
2013-10-11, De Geersalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 10:00 (English)
Opponent
Supervisors
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
List of papers
1. Cord blood monocyte subsets are similar to adult and show potent peptidoglycan-stimulated cytokine responses
Open this publication in new window or tab >>Cord blood monocyte subsets are similar to adult and show potent peptidoglycan-stimulated cytokine responses
2011 (English)In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 133, no 1, 41-50 p.Article in journal (Refereed) Published
Abstract [en]

P>Human monocytes can be divided into two major subpopulations, CD14++ CD16- and CD14+ CD16+ cells, which are suggested to play different roles in antimicrobial responses. In neonates, characteristics and functional responses of monocyte subsets have not previously been explored, and might contribute to the qualitative difference between neonatal and adult cytokine profiles. We report that at baseline, monocyte subsets in cord blood and adult peripheral blood are present in similar frequencies, and show similar expression of CD11c, CD80/CD86, CD163 and HLA-DR. In response to the bacterial ligand peptidoglycan, cord blood monocytes had high inherent capacity for production of the early-response cytokines with levels of tumour necrosis factor and interleukin-12p70 exceeding adult levels, and also a higher phosphorylation of p38-mitogen-activated protein kinase. The CD14+ CD16+ cells expressed more interleukin-12p70 than CD14++ CD16- cells and were present in a higher frequency in peptidoglycan-stimulated cord blood mononuclear cell cultures. Together, the behaviour of cord blood CD14+ CD16+ cells following peptidoglycan stimulation might indicate a qualitative difference between the neonatal antimicrobial response and that of the adult. In addition we found that serum factors in cord blood and adult sera affected cytokine production similarly, with the exception of tumour necrosis factor, regardless of the source of serum or cells. Overall, our data provide new insights into monocyte heterogeneity in cord blood and monocyte subset responses to a bacterial ligand at birth.

Keyword
CD14++CD16-cells, CD14+CD16+cells, interleukin-12p70, neonatal immunity, tumour necrosis factor
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-68518 (URN)10.1111/j.1365-2567.2011.03407.x (DOI)000289160000005 ()
Funder
Swedish Research Council, K2010-57X-15160-07-3
Note

4

Available from: 2012-01-05 Created: 2012-01-04 Last updated: 2017-12-08Bibliographically approved
2. Herpesvirus seropositivity in childhood associates with decreased monocyte-induced NK-cell IFN-γ production
Open this publication in new window or tab >>Herpesvirus seropositivity in childhood associates with decreased monocyte-induced NK-cell IFN-γ production
Show others...
2009 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 182, no 4, 2511-2517 p.Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-25536 (URN)10.4049/jimmunol.0801699 (DOI)000263126300082 ()19201907 (PubMedID)
Available from: 2008-10-16 Created: 2008-10-16 Last updated: 2017-12-13Bibliographically approved
3. Epstein-Barr Virus Co-infection in Children Boosts Cytomegalovirus-induced Differentiation of Natural Killer Cells
Open this publication in new window or tab >>Epstein-Barr Virus Co-infection in Children Boosts Cytomegalovirus-induced Differentiation of Natural Killer Cells
Show others...
(English)Manuscript (preprint) (Other academic)
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.

Keyword
CMV, EBV, co-infection, NK cell, NKG2C
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-93007 (URN)
Available from: 2013-08-28 Created: 2013-08-28 Last updated: 2013-08-30Bibliographically approved
4. CMV Seropositive Children Show Inhibition of In Vitro EBV Infection that is Associated with CD8+CD57+ T-cell Enrichment and IFN-g
Open this publication in new window or tab >>CMV Seropositive Children Show Inhibition of In Vitro EBV Infection that is Associated with CD8+CD57+ T-cell Enrichment and IFN-g
Show others...
(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
Children, EBV, CMV, B cell, T cell, IFN-γ
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-93008 (URN)
Available from: 2013-08-28 Created: 2013-08-28 Last updated: 2013-08-30Bibliographically approved

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