Influence of relative NK-DC abundance on placentation and its relation to epigenetic programming in the offspring.

Normal placentation relies on an efficient maternal adaptation to pregnancy. Within the decidua, natural killer (NK) cells and dendritic cells (DC) have a critical role in modulating angiogenesis and decidualization associated with pregnancy. However, the contribution of these immune cells to the placentation process and subsequently fetal development remains largely elusive. Using two different mouse models, we here show that optimal placentation and fetal development is sensitive to disturbances in NK cell relative abundance at the fetal-maternal interface. Depletion of NK cells during early gestation compromises the placentation process by causing alteration in placental function and structure. Embryos derived from NK-depleted dams suffer from intrauterine growth restriction (IUGR), a phenomenon that continued to be evident in the offspring on post-natal day 4. Further, we demonstrate that IUGR was accompanied by an overall reduction of global DNA methylation levels and epigenetic changes in the methylation of specific hepatic gene promoters. Thus, temporary changes within the NK cell pool during early gestation influence placental development and function, subsequently affecting hepatic gene methylation and fetal metabolism.

Pregnancy-specific glycoprotein 1 (PSG1) activates TGF-ß and prevents dextran sodium sulfate (DSS)-induced colitis in mice.

Transforming growth factor-ßs (TGF-ßs) are secreted from cells as latent complexes and the activity of TGF-ßs is controlled predominantly through activation of these complexes. Tolerance to the fetal allograft is essential for pregnancy success; TGF-ß1 and TGF-ß2 play important roles in regulating these processes. Pregnancy-specific ß-glycoproteins (PSGs) are present in the maternal circulation at a high concentration throughout pregnancy and have been proposed to have anti-inflammatory functions. We found that recombinant and native PSG1 activate TGF-ß1 and TGF-ß2 in vitro. Consistent with these findings, administration of PSG1 protected mice from dextran sodium sulfate (DSS)-induced colitis, reduced the secretion of pro-inflammatory cytokines, and increased the number of T regulatory cells. The PSG1-mediated protection was greatly inhibited by the coadministration of neutralizing anti-TGF-ß antibody. Our results indicate that proteins secreted by the placenta directly contribute to the generation of active TGF-ß and identify PSG1 as one of the few known biological activators of TGF-ß2.

Apoptotic DC-SIGN+ cells in normal human decidua.

BACKGROUND: Normal pregnancy and spontaneous abortion in humans and mice are associated with immune responses. The decidua harbors dendritic cells identifiable in humans by their expression of DC-SIGN. Because dendritic cells are essential for immune response regulation, decidual DC-SIGN+ cells may play a role in normal or pathological pregnancy outcomes. Previous reports suggested that DC interact with NK cells in decidua, although the functional significance of this phenomenon remains unknown. OBJECTIVE: We studied the presence of conjugates of DC-SIGN+ cells with CD56+ NK cells in normal human decidua. METHODS: Conjugates of DC-SIGN+ cells with CD56+ NK cells were studied in leukocyte suspensions of normal human decidua (6-11 weeks) by flow cytometry and confocal microscopy. The presence of apoptotic cells was determined by the TUNEL assay, incubation with annexin V and confocal microscopy in decidual leukocyte suspensions and by the TUNEL assay in decidual sections. RESULTS: We observed conjugates of decidual DC-SIGN+ cells with CD56+ NK cells (40.2±26.1% of all the DC-SIGN+ cells by flow cytometry and 52.3±10.2% by confocal microscopy). We also found that a proportion of DC-SIGN+ cells were in apoptosis, since they were TUNEL+ (40.2±7.2% of all DC-SIGN+ cells in decidual sections) and annexin V+ (34.4±15.2% in leukocyte suspensions). And sorted DC-SIGN+ cells had multilobulated nuclei. CONCLUSIONS: The conjugates of decidual DC-SIGN+ cells with CD56+ NK cells strongly suggest that these latter cells induce apoptosis in DC-SIGN+ cells during normal pregnancy. We discuss this possibility in the context of maternal-fetal tolerance.

Reduced proportion of decidual DC-SIGN+ cells in human spontaneous abortion.

Recent studies showed that some functions of decidual dendritic cells appear to be essential for pregnancy. In humans, decidual dendritic cells are identifiable by their expression of DC-SIGN. We compared the subpopulations of human decidual DC-SIGN+ cells from first-trimester normal pregnancies and spontaneous abortions by flow cytometry. In normal decidua, DC-SIGN+ cells expressed antigens associated with immature myeloid dendritic cells. In samples from spontaneous abortions, we detected decidual DC-SIGN+ cells with an antigen phenotype equivalent to that of DC-SIGN+ cells from normal pregnancies, but at a significantly lower proportion (P < 0.01). Our results support the hypothesis that dendritic cells play a role in normal or pathological human pregnancy outcomes.

The impact of dendritic cells on angiogenic responses at the fetal-maternal interface.

The success of mammalian pregnancy is highly dependent on the establishment of an adequate blood supply to support the metabolic demands of the growing embryo and fetus. New blood vessels develop from pre-existing vessels in a multi-step process called angiogenesis, which is tightly regulated in time and space and has proven to be crucial in several physiological situations such as wound healing, follicular development and cyclic endometrial growth. As in other tissues, the regulation of angiogenic responses in the decidua depends on a delicate balance between stimulatory and inhibitory signals. In particular, trophoblasts and decidual NK cells are well-recognized components of the uterine signaling network with a proven ability to produce growth factors and cytokines that modulate endothelial cell responsiveness during pregnancy. In mice and humans, dendritic cells are also considered an important regulatory component during pregnancy, mainly due to their role in the establishment of maternal immunologic tolerance. However, the recent finding that dendritic cell subsets can promote angiogenesis in a variety of physiopathological settings suggests that regulatory functions of these cells may go beyond the promotion of maternal tolerance, having impact on other processes such as decidualization and placentation and the vascular changes associated to them. Current evidence on dendritic cell-derived angiogenic signals and their potential implications in vascular development during gestation are reviewed and discussed herein.