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CD4+ CD25+ regulatory T cells in human pregnancy: Development of a Treg-MLC-ELISPOT suppression assay and indications of paternal specific Tregs
Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Obstetrics and gynecology. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Gynecology and Obstetrics in Linköping.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology.ORCID iD: 0000-0002-3993-9985
2007 (English)In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 120, no 4, 456-466 p.Article in journal (Refereed) Published
Abstract [en]

The current study was aimed at developing a one-way mixed leucocyte culture-enzyme-linked immunospot (MLC-ELISPOT) assay for the study of CD4 + CD25+ regulatory T (Treg) cells and applying this method in the study of antifetal immune reactions during human pregnancy. Twenty-one pregnant women and the corresponding fathers-to-be, and 10 non-pregnant control women and men, participated in the study. CD4+ CD25+ cells were isolated from peripheral blood mononuclear cells (PBMC) by immunomagnetic selection. Maternal/control PBMC were stimulated with paternal or unrelated PBMC in MLC. Secretion of interleukin-4 (IL-4) and interferon-γ (IFN-γ) from responder cells, with or without the presence of autologous Treg cells, was analysed by ELISPOT. PBMC from pregnant women showed increased secretion of IL-4 compared to controls. In pregnant and non-pregnant controls, Treg cells suppressed IFN-γ reactivity against paternal and unrelated alloantigens. Interestingly, T reg cells suppressed IL-4 secretion against paternal but not unrelated alloantigens during pregnancy. We have successfully developed a model for studying Treg cells in antifetal cytokine reactions during pregnancy. Results indicate that Treg cells contribute to strict regulation of both T helper type 1-like and type 2-like antifetal immune reactions. Interestingly, T helper type 2-like cells specific to unrelated alloantigens are able to escape the suppression of Treg cells, which would allow for IL-4, alongside CD4+ CD25+ Treg cells, to control potentially detrimental IFN-γ reactions during pregnancy. © 2007 Blackwell Publishing Ltd.

Place, publisher, year, edition, pages
2007. Vol. 120, no 4, 456-466 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-37719DOI: 10.1111/j.1365-2567.2006.02529.xLocal ID: 37846OAI: oai:DiVA.org:liu-37719DiVA: diva2:258568
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
In thesis
1. Regulatory T cells in human pregnancy
Open this publication in new window or tab >>Regulatory T cells in human pregnancy
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

During pregnancy, fetal tolerance has to be achieved without compromising the immune integrity of the mother. CD4+CD25highFoxp3+ regulatory cells (Tregs) have received vast attention as key players in immune regulation. However, the identification of human Tregs is complicated by their similarity to activated nonsuppressive T cells. The general aim of this thesis was to determine the antigen specificity, frequency, phenotype and function of Tregs in first to second trimester healthy and severe early-onset preeclamptic human pregnancy. Regarding antigen specificity, we observed that in healthy pregnant women, Tregs suppressed both TH1 and TH2 reactions when stimulated with paternal alloantigens but only TH1, not TH2 reactions when stimulated with unrelated alloantigens. Hence, circulating paternal-specific Tregs seem to be present during pregnancy. Further, by strictly defining typical Tregs (CD4dimCD25high) using flow cytometry, we could show that as a whole, the Treg population was reduced already during first trimester pregnancy as compared with non-pregnant women. This was in contrast to several previous studies and the discrepancy was most likely due to the presence of activated non-suppressive cells in pregnant women, showing similarities to the suppressive Tregs. Although deserving confirmation in a larger sample, severe early-onset preeclampsia did not seem to be associated with alterations in the circulating Treg population. The circulating Treg population was controlled by hormones which, alike pregnancy, reduced the frequency of Foxp3 expressing cells. Yet, in vitro, pregnancy Tregs were highly suppressive of pro-inflammatory cytokine secretion and showed an enhanced capability of secreting immune modulatory cytokines such as IL-4 and IL-10, as well as IL-17, indicating an increased plasticity of pregnancy Tregs. At the fetalmaternal interface during early pregnancy, Tregs, showing an enhanced suppressive and proliferating phenotype, were enriched as compared with blood. Further, CCR6- TH1 cells, with a presumed moderate TH1 activity were enhanced, whereas pro-inflammatory TH17 and CCR6+ TH1 cells were fewer as compared with blood. This thesis adds to and extends the view of Tregs as key players in immune regulation during pregnancy. In decidua, typical Tregs seem to have an important role in immune suppression whereas systemically, Tregs are under hormonal control and are numerically suppressed during pregnancy. Further, circulating pregnancy Tregs show reduced expression of Foxp3 and an increased degree of cytokine secretion and thereby also possibly plasticity. This would ensure systemic defense against infections with simultaneous tolerance at the fetal-maternal interface during pregnancy.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2010. 156 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1163
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-53619 (URN)978‐91‐7393‐460‐2 (ISBN)
Public defence
2010-01-22, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
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Available from: 2010-01-26 Created: 2010-01-26 Last updated: 2011-02-23Bibliographically approved

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Mjösberg, JennyBerg, GöranErnerudh, JanEkerfelt, Christina

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