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FOXP3+ CD4 T-cell maturity and responses to microbial stimulation alter with age and associate with early-life gut colonization
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.
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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2016 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 138, no 3, 905-908 p.Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
2016. Vol. 138, no 3, 905-908 p.
National Category
Immunology
Research subject
Molecular Bioscience
Identifiers
URN: urn:nbn:se:su:diva-133987DOI: 10.1016/j.jaci.2016.04.027ISI: 000385496000031OAI: oai:DiVA.org:su-133987DiVA: diva2:974371
Available from: 2016-09-26 Created: 2016-09-26 Last updated: 2017-04-21Bibliographically approved
In thesis
1. Infant gut microbiota, immune responses and allergic disease during childhood
Open this publication in new window or tab >>Infant gut microbiota, immune responses and allergic disease during childhood
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The early-life microbiota is important for postnatal immune maturation and implied in immune mediated diseases. The aim of this work was to study specific species of bacteria in the gut microbiota and relate them to immune function and allergic disease during childhood.

In paper I we investigated gut bacteria in feces from infants included in a prospective allergy cohort. We found that children with non-allergic parents were more likely to be colonized with a group of lactobacilli. Further, lactobacilli colonization was more prevalent in children remaining non-allergic, regardless of allergic heredity. In paper II we related the infant gut bacteria to immune function at two years of age. Infant Staphylococcus (S.) aureus colonization associated with increased immune responsiveness, whereas co-colonization with S. aureus and lactobacilli associated with reduced responses. In paper III we investigated T regulatory (Treg) cell phenotype and cytokine production during childhood, and related S. aureus and lactobacilli colonization to Treg phenotype at the age of two. The Treg population matured with age, regarding phenotype and cytokine production. Furthermore, infant S. aureus colonization associated with Treg phenotype at the age of two. In paper IV we investigated the in vitro peripheral blood mononuclear cells responses to soluble factors produced by lactobacilli and S. aureus. Both T- and natural killer cells responded with cytokine production, degranulation and proliferation after S. aureus and simultaneous culture with lactobacilli could dampen the S. aureus-induced responses.

Taken together this thesis shows that the gut microbiota is altered in children who develop allergies, and that early life bacteria associate with immune function. Our in vitro findings support that lactobacilli modulate immune maturation and responses, and that early lactobacilli-colonization may be important for a properly regulated maturation of the immune system.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2014. 82 p.
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-108425 (URN)978-91-7649-036-5 (ISBN)
Public defence
2014-11-28, De Geersalen, Geovetenskapens hus, Svante Arrhenius väg 14, 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: 2014-11-06 Created: 2014-10-23 Last updated: 2016-09-27Bibliographically approved
2. Immune maturation and lymphocyte characteristics in relation to early gut bacteria exposure
Open this publication in new window or tab >>Immune maturation and lymphocyte characteristics in relation to early gut bacteria exposure
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

At birth, the immune system is immature and the gut microbiota influences immune maturation. Staphylococcus aureus (S. aureus) and lactobacilli are part of the neonatal gut microbiota and have seemingly opposite effects on the immune system. S. aureus is a potent immune activator and early-life colonization associates with higher immune responsiveness later in life. Lactobacilli-colonization associates with reduced allergy-risk and lower immune responsiveness. Further, lactobacilli modulate immune-activation and have probiotic features.

Here, we investigated S. aureus-induced activation of human lymphocytes, including T regulatory cells (Tregs), conventional T-cells (CD4+ and CD8+), unconventional T-cells (γδ T-cells and MAIT-cells) and NK-cells from children and adults, together with the modulatory effect of lactobacilli on immune-activation. Further, early-life colonization with these bacteria was related to lymphocyte-maturation, plasma cytokine- and chemokine-levels and allergy. 

S. aureus cell free supernatant (CFS) and staphylococcal enterotoxin (SE) A induced an increased percentage of FOXP3+ Tregs and of CD161+, IL-10+, IFN-γ+ and IL-17A+ Tregs (Paper I). The same pattern was observed in children with a lower degree of activation, possibly due to lower CD161-expression and poor activation of naive T-cells (Paper II). S. aureus-CFS induced IFN-γ-expression, proliferation and cytotoxic capacity in conventional and unconventional T-cells, and NK-cells. SEA, but not SEH, induced activation of unconventional T-cells and NK-cells by unknown mechanism(s) (Paper III, extended data). Lactobacilli-CFS reduced S. aureus-induced lymphocyte activation without the involvement of IL-10, Tregs or monocytes, but possibly involving lactate (Paper III). Early-life colonization with S. aureus associated with increased percentages of CD161+ and IL-10+ Tregs while lactobacilli-colonization negatively correlated with the percentage of IL-10+ Tregs later in life (Paper II). Allergic disease in childhood associated with double allergic heredity, being born wintertime and with higher plasma levels of TH2-, TH17- and TFH-related chemokines early in life. Lactobacilli-colonization associated with lower prevalence of allergy, reduced chemokine-levels and increased levels of IFN-γ in plasma (Paper IV).   

This thesis provides novel insights into S. aureus- and SE-mediated activation of Tregs, unconventional T-cells and NK-cells and suggests an overall impairment of immune-responsiveness towards this bacterium in children. Further, S. aureus-colonization may influence the maturation of peripheral Tregs. Our data show that lactobacilli potently dampen lymphocyte-activation in vitro and that colonization associates with Treg-responsiveness, altered plasma cytokine- and chemokine-levels and with remaining non-allergic, thereby supporting the idea of lactobacilli as important immune-modulators.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2016. 125 p.
Keyword
Allergy, cell-free supernatant, chemokines, colonization, cytokines, FOXP3, immune-maturation, lactobacilli, lymphocytes, NK-cells, Staphylococcus aureus, unconventional T-cells
National Category
Immunology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-134054 (URN)978-91-7649-504-9 (ISBN)978-91-7649-505-6 (ISBN)
Public defence
2016-11-25, sal E306, Arrheniuslaboratorierna, Svante Arrhenius väg 20 C, Stockholm, 09:30 (English)
Opponent
Supervisors
Note

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

 

Available from: 2016-11-01 Created: 2016-09-28 Last updated: 2016-10-24Bibliographically approved

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Björkander, SophiaJohansson, Maria A.Lasaviciute, GintareSverremark-Ekström, Eva
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