Lineage, Maturity, and Phenotype of Uterine Murine Dendritic Cells Throughout Gestation Indicate a Protective Role in Maintaining Pregnancy

Charité, Department of Internal Medicine, Biomedizinisches Forschungszentrum, Campus Virchow, Humboldt University of Berlin, 13353 Berlin, Germany.
Biology of Reproduction (Impact Factor: 3.32). 05/2004; 70(4):1018-23. DOI: 10.1095/biolreprod.103.022640
Source: PubMed


Dendritic cells (DCs) are known to play a major role in the induction, maintenance, and regulation of immune responses. Recently, DCs have been described to be present at the feto-maternal interface in human decidua. However, only limited information is available about DC presence, phenotype, and--more importantly--function throughout gestation. Thus, we analyzed local (uterine) and systemic (blood) DCs in a murine model. DBA/2J mated CBA/J females with vaginal plugs were separated and killed on Gestation Days (GDs) 1.5, 3.5, 5.5, 6.5, 7.5, 8.5, 10.5, 13.5, 15.5, or 17.5. Frequency of uterine and blood CD11c+ DC, phenotype (coexpression of CD8alpha and major histocompatibility complex class II [MHC II] antigens), and presence of intracellular cytokines (interleukins 12 and 10) were determined by flow cytometry. The morphology of DC in the pregnant uterus was evaluated by immunohistochemistry. In uterus, the relative number of CD11c+ cells increased from GD 5.5, reaching a plateau on GD 9.5 until GD 17.5, while a transient peak of systemic CD11c+ cells was found on GD 8.5 and 10.5. The vast majority of uterine DCs were CD8alpha- and thus, belonged to the myeloid lineage. Interestingly, a significant peak of lymphoid DC was present on GD 1.5 and 5.5. Further, significantly more intracellular interleukin 10 than interleukin 12 was present in CD11c+ cells. Interestingly, mature DCs (MHC II+) were diminished from GD 5.5 to 8.5. Characterization of CD11c+ cell kinetics in uterus and blood reveals variation of phenotype during pregnancy, pointing toward an eminent immunoregulatory role of DCs throughout gestation at the feto-maternal interface.

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    • "Schumacher and Zenclussen HO-1 modulates immunity towards allo-antigens (Kammerer et al., 2003; Blois et al., 2004). In contrast, abortions in mice are associated with an increased number of mature, IL- 12-producing DCs (Blois et al., 2005). "
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    ABSTRACT: The heme-degrading enzyme heme oxygenase-1 (HO-1) has cytoprotective, antioxidant and anti-inflammatory properties. Moreover, HO-1 is reportedly involved in suppressing destructive immune responses associated with inflammation, autoimmune diseases, and allograft rejection. During pregnancy, maternal tolerance to foreign fetal antigens is a prerequisite for successful embryo implantation and fetal development. Here, HO-1 has been implicated in counteracting the overwhelming inflammatory immune responses towards fetal allo-antigens, thereby contributing to fetal acceptance. Accordingly, HO-1 ablation negatively impacts the critical steps of pregnancy such as fertilization, implantation, placentation, and fetal growth. In the present review, we summarize recent data on the immune modulatory capacity of HO-1 towards allo-antigens expressed by the semi-allogeneic fetus and organ allografts. In this regard, HO-1 has been shown to promote alloantigen tolerance by blocking dendritic cell (DC) maturation resulting in reduced T cell responses and increased numbers of regulatory T cells. Moreover, HO-1 is suggested to shift the uterine cytokine milieu towards a protective Th2 profile and protects fetal tissue from apoptosis by upregulating anti-apoptotic molecules. Thus, HO-1 is not only a pivotal regulator of the initial steps of pregnancy; but also, an important player in supporting the maternal immune system in tolerating the fetus.
    Frontiers in Pharmacology 12/2014; 5. DOI:10.3389/fphar.2014.00288 · 3.80 Impact Factor
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    • "These results are in agreement with published results in the mouse where a preferential increase of uterine monocytes over other cell types has been observed in pregnancy [50], [51]. Likewise, Blois et al. [52] have found an increase in CD11c+ uterine cells (mostly myeloid DC) isolated by tissue digestion during gestation. Our results are also in agreement with the small frequency and numbers of NKT cells found at the fetal-maternal interface by Ito et al. [51], [53]. "
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    ABSTRACT: Despite much interest in the mechanisms regulating fetal-maternal interactions, information on leukocyte populations and major cytokines present in uterus and placenta remains fragmentary. This report presents a detailed and quantitative study of leukocyte populations at the mouse fetal-maternal interface, including a comparison between pregnancies from syngeneic and allogeneic crosses. Our results provide evidence for drastic differences not only in the composition of leukocyte populations in the uterus during pregnancy, but also between uterine and placental tissues. Interestingly, we have observed a significant decrease in the number of myeloid Gr1+ cells including monocytes, and myeloid CD11c+ cells including DCs in placenta from an allogeneic pregnancy. In addition, we have compared the expression levels of a panel of cytokines in non-pregnant (NP) or pregnant mouse uterus, in placenta, or in their isolated resident leukocytes. Qualitative and quantitative differences have emerged between NP, pregnant uterus and placenta. Unexpectedly, IL-9 was the major cytokine in NP uterus, and was maintained at high levels during pregnancy both in uterus and placenta. Moreover, we have found that pregnancy is associated with an increase in uterine IL-1a and a significant decrease in uterine G-CSF and GM-CSF. Comparing allogeneic versus syngeneic pregnancy, less allogeneic placental pro-inflammatory cytokines CCL2 (MCP-1), CXCL10 (IP-10) and more IL1-α in whole uterus was reproducibly observed. To our knowledge, this is the first report showing a detailed overview of the leukocyte and cytokine repertoire in the uterus of virgin females and at the fetal-maternal interface, including a comparison between syngeneic and allogeneic pregnancy. This is also the first evidence for the presence of IL-9 in NP uterus and at the maternal-fetal interface, suggesting a major role in the regulation of local inflammatory or immune responses potentially detrimental to the conceptus.
    PLoS ONE 09/2014; 9(9):e107267. DOI:10.1371/journal.pone.0107267 · 3.23 Impact Factor
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    • "In many cases, they transport bacteria or other potential pathogens with them, and they present these microbial cells to the lymphocytes. The uterine decidua has a population of resident lymphocytes, and these cells are essential for normal implantation and the lack of rejection of the fetus (Blois et al., 2004; Juretic et al., 2004; Laskarin et al., 2007; Zarnani et al., 2008). So the oral cavity has a mucosa with associated dendritic cells, and the placenta has a lymphoid region capable of receiving dendritic cells. "
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    Frontiers in Genetics 08/2014; 5:282. DOI:10.3389/fgene.2014.00282
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