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Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17θ-estradiol
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
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2009 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 183, no 1, 759-769 p.Article in journal (Refereed) Published
Abstract [en]

CD4+CD25high regulatory T cells (Tregs) are implicated in the maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent, and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim of this study was to determine the frequency, phenotype, and function of circulating Tregs in the second trimester of human pregnancy and the influence of progesterone and 17β-estradiol on Treg phenotype and frequency. Based on expressions of Foxp3, CD127, and HLA-DR as determined by multicolor flow cytometry, we defined a proper CD4dimCD25high Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester of pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4+ population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17β-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4dimCD25highFoxp3+ cells in PBMC from nonpregnant women. By coculturing FACS-sorted Tregs and autologous CD4+CD25 responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as nonpregnant women in terms of suppressing IL-2, TNF-, and IFN- secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Furthermore, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need reevaluation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Place, publisher, year, edition, pages
2009. Vol. 183, no 1, 759-769 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-53104DOI: 10.4049/jimmunol.0803654ISI: 000275119400082PubMedID: 19535629OAI: oai:DiVA.org:liu-53104DiVA: diva2:286812
Available from: 2010-01-26 Created: 2010-01-15 Last updated: 2017-12-12Bibliographically approved
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, JennySvensson, JuditJohansson, EmmaHellström, LottaCasas, RosauraJenmalm, MariaJönsson, Jan-IngvarBerg, GöranErnerudh, Jan

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Mjösberg, JennySvensson, JuditJohansson, EmmaHellström, LottaCasas, RosauraJenmalm, MariaJönsson, Jan-IngvarBerg, GöranErnerudh, Jan
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Clinical ImmunologyFaculty of Health SciencesGeriatricPediatricsCell BiologyObstetrics and gynecologyDepartment of Gynecology and Obstetrics in LinköpingDepartment of Clinical Immunology and Transfusion Medicine
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