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Regulatory T cells in human pregnancy
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
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: urn:nbn:se:liu:diva-53619ISBN: 978‐91‐7393‐460‐2 OAI: oai:DiVA.org:liu-53619DiVA: diva2:290259
Public defence
2010-01-22, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2010-01-26 Created: 2010-01-26 Last updated: 2011-02-23Bibliographically approved
List of papers
1. CD4+ CD25+ regulatory T cells in human pregnancy: Development of a Treg-MLC-ELISPOT suppression assay and indications of paternal specific Tregs
Open this publication in new window or tab >>CD4+ CD25+ regulatory T cells in human pregnancy: Development of a Treg-MLC-ELISPOT suppression assay and indications of paternal specific Tregs
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-37719 (URN)10.1111/j.1365-2567.2006.02529.x (DOI)37846 (Local ID)37846 (Archive number)37846 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
2. Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17θ-estradiol
Open this publication in new window or tab >>Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17θ-estradiol
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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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-53104 (URN)10.4049/jimmunol.0803654 (DOI)000275119400082 ()19535629 (PubMedID)
Available from: 2010-01-26 Created: 2010-01-15 Last updated: 2017-12-12Bibliographically approved
3. Circulating CD4dimCD25highFOXP3+ regulatory T cells in severe early-onset preeclampsia
Open this publication in new window or tab >>Circulating CD4dimCD25highFOXP3+ regulatory T cells in severe early-onset preeclampsia
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Preeclampsia is an inflammatory condition suggested to involve regulatory CD4+CD25high T helper cell (Treg) disturbances. However, the importance of Tregs in early-onset preeclampsia, associated with increased disease severity and possibly representing a more distinct placental disease, remains unclear. We recently showed that by defining Tregs as CD4dimCD25high cells, the risk of including activated non-Tregs, being more prominent in the circulation during pregnancy, is avoided. The aim of this study was to determine, using updated Treg markers and flow cytometric gating strategies, the frequency and phenotype of circulating Tregs from women with severe early-onset preeclampsia (n=10) as compared with healthy pregnant (n=20) and nonpregnant (n=20) women. The frequency of CD4dimCD25high cells and the expression of FOXP3 was similar in healthy and preeclamptic pregnancy. However, the occurrence of CTLA-4+ and HLA-DR+ cells in the Treg population from preeclamptic women tended to be higher than in healthy pregnant women, indicating alterations in Treg functionality in preeclampsia. Further, the Treg population from healthy pregnant, but not preeclamptic, women tended to be enriched for CCR4+ and CD45R0+ cells as compared with nonpregnant women. In conclusion, although the findings do not support a role for diminished circulating Treg frequency in severe early-onset preeclampsia, the study suggests functional alterations related to Treg suppression, activation and migration mechanisms in this subgroup of preeclamptic women.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-53617 (URN)
Available from: 2010-01-26 Created: 2010-01-26 Last updated: 2010-01-26
4. FOXP3+ regulatory T cells, T helper 1, T helper 2 and T helper 17 cells in human early pregnancy decidua
Open this publication in new window or tab >>FOXP3+ regulatory T cells, T helper 1, T helper 2 and T helper 17 cells in human early pregnancy decidua
2010 (English)In: Biology of Reproduction, ISSN 0006-3363, E-ISSN 1529-7268, Vol. 82, no 4, 698-705 p.Article in journal (Refereed) Published
Abstract [en]

In pregnancy, the decidua is infiltrated by leukocytes promoting fetal development without causing immunological rejection. Murine regulatory T (Treg) cells are known to be important immune regulators at this site. The aim of the study was to characterize the phenotype and origin of Treg cells and determine the quantitative relationship between Treg, T-helper type 1 (TH1), TH2, and TH17 cells in first-trimester human decidua. Blood and decidual CD4+ T cells from 18 healthy first-trimester pregnant women were analyzed for expression of Treg-cell markers (CD25, FOXP3, CD127, CTLA4, and human leukocyte antigen-DR [HLA-DR]), chemokine receptors (CCR4, CCR6, and CXCR3), and the proliferation antigen MKI67 by six-color flow cytometry. Treg cells were significantly enriched in decidua and displayed a more homogenous suppressive phenotype with more frequent expression of FOXP3, HLA-DR, and CTLA4 than in blood. More decidual Treg cells expressed MKI67, possibly explaining their enrichment at the fetal-maternal interface. Using chemokine receptor expression profiles of CCR4, CCR6, and CXCR3 as markers for TH1, TH2, and TH17 cells, we showed that TH17 cells were nearly absent in decidua, whereas TH2-cell frequencies were similar in blood and decidua. CCR6+ TH1 cells, reported to secrete high levels of interferon gamma (IFNG), were fewer, whereas the moderately IFNG-secreting CCR6 TH1 cells were more frequent in decidua compared with blood. Our results point toward local expansion of Treg cells and low occurrence of TH17 cells. Furthermore, local, moderate TH1 activity seems to be a part of normal early pregnancy, consistent with a mild inflammatory environment controlled by Treg cells.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-53616 (URN)10.1095/biolreprod.109.081208 (DOI)000275814400007 ()20018909 (PubMedID)
Note

Published online before print December 16, 2009,

Available from: 2010-01-26 Created: 2010-01-26 Last updated: 2017-12-12

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Mjösberg, Jenny

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