liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
The Human Fetal Placenta Promotes Tolerance against the Semiallogeneic Fetus by Inducing Regulatory T Cells and Homeostatic M2 Macrophages
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0003-2245-3396
Show others and affiliations
2015 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 194, no 4, 1534-1544 p.Article in journal (Refereed) Published
Abstract [en]

A successful pregnancy requires that the maternal immune system is instructed to a state of tolerance to avoid rejection of the semiallogeneic fetal-placental unit. Although increasing evidence supports that decidual (uterine) macrophages and regulatory T cells (Tregs) are key regulators of fetal tolerance, it is not known how these tolerogenic leukocytes are induced. In this article, we show that the human fetal placenta itself, mainly through trophoblast cells, is able to induce homeostatic M2 macrophages and Tregs. Placental-derived M-CSF and IL-10 induced macrophages that shared the CD14(+)CD163(+)CD206(+)CD209(+) phenotype of decidual macrophages and produced IL-10 and CCL18 but not IL-12 or IL-23. Placental tissue also induced the expansion of CD25(high)CD127(low)Foxp3(+) Tregs in parallel with increased IL-10 production, whereas production of IFN-gamma (Th1), IL-13 (Th2), and IL-17 (Th17) was not induced. Tregs expressed the suppressive markers CTLA-4 and CD39, were functionally suppressive, and were induced, in part, by IL-10, TGF-beta, and TRAIL. Placental-derived factors also limited excessive Th cell activation, as shown by decreased HLA-DR expression and reduced secretion of Th1-, Th2-, and Th17-associated cytokines. Thus, our data indicate that the fetal placenta has a central role in promoting the homeostatic environment necessary for successful pregnancy. These findings have implications for immune-mediated pregnancy complications, as well as for our general understanding of tissue-induced tolerance.

Place, publisher, year, edition, pages
American Association of Immunologists , 2015. Vol. 194, no 4, 1534-1544 p.
National Category
Clinical Medicine Immunology in the medical area
Identifiers
URN: urn:nbn:se:liu:diva-115319DOI: 10.4049/jimmunol.1401536ISI: 000349462000017PubMedID: 25560409OAI: oai:DiVA.org:liu-115319DiVA: diva2:795093
Note

Funding Agencies|Medical Research Council [K2013-61X-22310-01-4]

Available from: 2015-03-13 Created: 2015-03-13 Last updated: 2017-12-04
In thesis
1. Immune regulation at the fetal‐maternal interface with focus on decidual macrophages
Open this publication in new window or tab >>Immune regulation at the fetal‐maternal interface with focus on decidual macrophages
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A successful pregnancy requires that the maternal immune system adapts to tolerate the semi-allogeneic fetal-placental unit. This adaptation mainly occurs locally, i.e. at the fetal-maternal interface, where fetal-derived tissues come into close contact with maternal cells in the uterine endometrium (called decidua during pregnancy). Macrophages and regulatory T (Treg) cells are maternal immune cells that are enriched in the decidua and they likely play a central role in promoting fetal tolerance. However, the precise function of decidual macrophages and the factors regulating both macrophages and Treg cells in humans are unknown. The aim of this thesis was to characterize the phenotype and function of decidual macrophages from first trimester human pregnancy and to identify factors responsible for inducing tolerogenic properties in both decidual macrophages and Treg cells. CD14+ decidual macrophages showed characteristics of immune suppressive or homeostatic macrophages (expression of CD163, CD206 and CD209), mainly produced immunosuppressive cytokines, like IL-10 and IL-35, while levels of inflammatory cytokines, for instance IL-12 and IL-23, were low. Decidual macrophages also induced the expansion of CD25highFoxp3+ Treg cells, but not of Th1, Th2 and Th17 cells, in vitro. In addition, decidual macrophages preferentially secreted the monocyte- and Treg cell-associated chemokines CCL2 and CCL18, while Th1-, Th2- and Th17-related chemokines were produced at low levels. These results suggest that decidual macrophages contribute to create the unique decidual cell composition and a tolerogenic immune environment that is compatible with fetal development. Further, by comparing decidual macrophages with different in vitro macrophage subsets, we showed that M-CSF and IL-10, but not GM-CSF, Th1 or Th2 stimuli, induced macrophages that resemble decidual macrophages in terms of cell surface marker expression, cytokine andchemokine production and gene expression profile. First trimester placental tissue, in particular placental trophoblast cells, was identified as an important source of M-CSF and IL-10. We also demonstrated that human fetal-derived placental tissue can induce the characteristics of decidual macrophages (CD163+CD206+CD209+IL-10+CCL18+) and the selective expansion of functionally suppressive CD25highFoxp3+ Treg cells, the latter partly mediated through IL-10, TGF-β and TRAIL. The placenta also limited activation of Th cells, for instance by generally reduced cytokine production. Our data show that the placenta has a unique ability to induce tolerogenic immune cells with a reduced inflammatory potential, which is essential for maintaining tissue integrity and preventing inflammation-induced fetal loss.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 150 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1448
National Category
Immunology Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-117183 (URN)10.3384/diss.diva-117183 (DOI)978-91-7519-117-1 (ISBN)
Public defence
2015-05-22, Linden, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2015-04-21 Created: 2015-04-21 Last updated: 2016-04-24Bibliographically approved

Open Access in DiVA

fulltext(1502 kB)410 downloads
File information
File name FULLTEXT01.pdfFile size 1502 kBChecksum SHA-512
ef587f45cc76b28d8d9e90752a13cbad8f4f832c31e641a3faf0d959f482f38f2c53c057863a85889a26ab5137410385feabf88e05b372f90ec67c98a3f949c3
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Authority records BETA

Svensson, JuditBhai Mehta, RatneshLindau, RobertMirrasekhian, ElaheRodriguez-Martinez, HeribertoBerg, GöranJenmalm, MariaErnerudh, Jan

Search in DiVA

By author/editor
Svensson, JuditBhai Mehta, RatneshLindau, RobertMirrasekhian, ElaheRodriguez-Martinez, HeribertoBerg, GöranJenmalm, MariaErnerudh, Jan
By organisation
Division of Neuro and Inflammation ScienceFaculty of Medicine and Health SciencesDivision of Cell BiologyFaculty of Health SciencesDivision of Clinical SciencesDepartment of Gynaecology and Obstetrics in LinköpingDepartment of Clinical Immunology and Transfusion Medicine
In the same journal
Journal of Immunology
Clinical MedicineImmunology in the medical area

Search outside of DiVA

GoogleGoogle Scholar
Total: 410 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 258 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf