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
Immune regulation at the fetal‐maternal interface with focus on decidual macrophages
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-117183DOI: 10.3384/diss.diva-117183ISBN: 978-91-7519-117-1 (print)OAI: oai:DiVA.org:liu-117183DiVA: diva2:806740
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
List of papers
1. Macrophages at the fetal-maternal interface express markers of alternative activation and are induced by M-CSF and IL-10
Open this publication in new window or tab >>Macrophages at the fetal-maternal interface express markers of alternative activation and are induced by M-CSF and IL-10
Show others...
2011 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 187, no 7, 3671-3682 p.Article in journal (Refereed) Published
Abstract [en]

During pregnancy, the maternal immune system is challenged by the presence of the fetus, which must be tolerated despite being semiallogeneic. Uterine mucosal (or decidual) macrophages (Mϕ), one of the major leukocyte populations at the fetal–maternal interface, have been implicated in fetal tolerance, but information regarding their regulation is scarce. In this study, we investigated the role of several factors potentially involved in the differentiation and polarization of decidual Mϕ with an in vitro Mϕ differentiation model. By using flow cytometry, we showed that M-CSF and IL-10 were potent inducers of M2 (immunoregulatory) Mϕ markers expressed on human decidual Mϕ (CD14, CD163, CD206, CD209). In contrast, proinflammatory stimuli, and unexpectedly also the Th2-associated IL-4 and IL-13, induced different patterns of expression, indicating that a Th2-dominated environment is not required for decidual Mϕ polarization. M-CSF/IL-10–stimulated and decidual Mϕ also showed similar cytokine secretion patterns, with production of IL-10 as well as IL-6, TNF, and CCL4. Conversely, the proinflammatory, LPS/IFN-γ–stimulated Mϕ produced significantly higher levels of TNF and no IL-10. We also used a gene array with 420 Mϕ-related genes, of which 100 were previously reported to be regulated in a global gene expression profiling of decidual Mϕ, confirming that M-CSF/IL-10–induced Mϕ are closely related to decidual Mϕ. Taken together, our results consistently point to a central role for M-CSF and in particular IL-10 in the shaping of decidual Mϕ with regulatory properties. These cytokines may therefore play an important role in supporting the homeostatic and tolerant immune milieu required for a successful pregnancy.

Place, publisher, year, edition, pages
American Association of Immunologists, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-73353 (URN)10.4049/jimmunol.1100130 (DOI)000295036400026 ()21890660 (PubMedID)
Available from: 2012-01-02 Created: 2012-01-02 Last updated: 2017-12-08
2. Decidual macrophages contribute to the unique leukocyte composition at the fetal-maternal interface by production of IL-35, induction of Treg cells and production of homeostatic chemokines
Open this publication in new window or tab >>Decidual macrophages contribute to the unique leukocyte composition at the fetal-maternal interface by production of IL-35, induction of Treg cells and production of homeostatic chemokines
Show others...
2015 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Reproductive success depends on the ability of the maternal immune system to adapt in order to tolerate and support the growing semi-allogenic fetus. Macrophages, being a major leukocyte population in the uterine mucosa (decidua), may play a central role in promoting the unique composition and regulatory phenotype of leukocytes that is characteristic for the fetal-maternal interface. We show that decidual macrophages display a predominantly immune regulatory gene profile and produce the immunosuppressive cytokine IL-35 but no other members of the IL-12 family (IL-12, IL-23 and IL-27). Decidual macrophages also promoted the selective expansion of CD25highFoxp3+ Tregs but not of Tbet+ Th1, GATA-3+ Th2 and Rorγt+ Th17 cells. In addition, these macrophages preferentially secreted the monocyte- and Treg-associated chemokines CCL2 and CCL18, while Th1-, Th2- and Th17-related chemokines were produced at low levels. Among in vitro macrophages, distinct chemokine profiles were observed; IL-4/13 upregulated Th2-associated chemokines (CCL17, CCL22, CCL26) while LPS/IFNγ upregulated Th1-associated chemokines (CXCL9, CXCL10, CXCL11, CCL5). M(IL-10) macrophages (induced by M-CSF and IL-10) showed a chemokine profile similar to that of decidual macrophages, as shown by gene expression and protein analysis. By using M(IL-10) macrophages as a model of decidual macrophages, we show that these cells promote the recruitment of CD14+ monocytes, while migration of several lymphocyte populations was unaltered or prevented. These data implicate decidual macrophages as critical regulators of the decidual leukocyte composition and phenotype that is associated with successful reproduction.

National Category
Immunology Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-117182 (URN)
Available from: 2015-04-21 Created: 2015-04-21 Last updated: 2016-03-23Bibliographically approved
3. The Human Fetal Placenta Promotes Tolerance against the Semiallogeneic Fetus by Inducing Regulatory T Cells and Homeostatic M2 Macrophages
Open this publication in new window or tab >>The Human Fetal Placenta Promotes Tolerance against the Semiallogeneic Fetus by Inducing Regulatory T Cells and Homeostatic M2 Macrophages
Show others...
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
National Category
Clinical Medicine Immunology in the medical area
Identifiers
urn:nbn:se:liu:diva-115319 (URN)10.4049/jimmunol.1401536 (DOI)000349462000017 ()25560409 (PubMedID)
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

Open Access in DiVA

fulltext(7573 kB)19992 downloads
File information
File name FULLTEXT01.pdfFile size 7573 kBChecksum SHA-512
e334ca19f8310b765156ab0467a4571dca9cd121023640dbab69fcd59d3d2c535c798129e5365912eb9f76d059b45ee321a6837c9d04cc7b73ab8e42b24e2b03
Type fulltextMimetype application/pdf
omslag(6565 kB)12 downloads
File information
File name COVER01.pdfFile size 6565 kBChecksum SHA-512
a848d8ba2193827256c0a95a33c36688b9bb17def6498a21e8fddcae521264fbaeac01494219723f964c39a87c737121ae6705145ef03a935346311e8afe1c1f
Type coverMimetype application/pdf

Other links

Publisher's full text

Authority records BETA

Svensson‐Arvelund, Judit

Search in DiVA

By author/editor
Svensson‐Arvelund, Judit
By organisation
Department of Clinical and Experimental MedicineFaculty of Health Sciences
ImmunologyClinical Medicine

Search outside of DiVA

GoogleGoogle Scholar
Total: 19992 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
isbn
urn-nbn

Altmetric score

doi
isbn
urn-nbn
Total: 803 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