ReviewPLACENTA

Immune responses at the maternal-fetal interface

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Science Immunology  11 Jan 2019:
Vol. 4, Issue 31, eaat6114
DOI: 10.1126/sciimmunol.aat6114

Figures

  • Fig. 1 Comparison of human and mouse placentation.

    (Left) Before placentation, the blastocysts of humans and mice are similar. (Middle and right) However, upon implantation, placental development progresses differently. (Top middle) After blastocyst implantation, the human SYN layer burrows into the maternal decidua. By the third week of gestation, the definitive human placenta is formed and is composed of villous trees. However, at this stage of human pregnancy, the fetal-derived placenta does not directly contact maternal blood. (Top right) EVTs anchor the villi to the decidua and are involved in the remodeling of the spiral arteries to flood the IVS with maternal blood toward the end of the first trimester of pregnancy. The surface of the villi is covered by the SYN layer, which directly contacts the maternal blood and facilitates the transport of nutrients, gases, and waste across the placental barrier. Underlying the SYN layer are mononucleated CTBs that can either fuse to replenish the syncytial layer or differentiate into EVTs. By contrast, mouse placental development and organization are different from those in humans. (Bottom middle) Upon implantation, the trophectoderm differentiates, and trophoblast giant cells encapsulate the developing mouse embryo. Halfway through gestation, the definitive mouse placenta is fully formed and functional, where (bottom right) the folded villi form a labyrinth structure that becomes perfused with maternal blood. The trophoblast giant cells channel maternal blood from the decidua through the spongiotrophoblast layer (a structure not present in the human placenta) toward the labyrinth zone. In the labyrinth zone, the maternal blood makes contact with the CTBs that overlay two separate layers of SYNs.

    CREDIT: A. KITTERMAN/SCIENCE IMMUNOLOGY
  • Fig. 2 Timeline of human and mouse placentation.

    The human early blastocyst forms around day 4 and is marked by the development of the trophectoderm—the first differentiation event in mammalian development. The primitive IVS forms around days 8 to 9 from the coalescence of vacuoles forming within the SYN mass (creating lacunae). In between the lacunae are columns of SYN (trabeculae), which are invaded by CTB around day 12 to form nascent villi. Around day 15, the CTB invade the decidua (a task previously performed by the SYN for implantation). By day 21, the definitive placenta is formed. However, maternal blood does not flood the IVS until weeks 10 to 12. By contrast, the gestational period of mice lasts just 20 days. Other differences between human and mice include the development of the choriovitelline placenta at day 8. This primitive placenta (not formed in human gestation) is composed of the juxtaposition of the yolk sac against the maternal tissues and blood vessels. At days 11 to 12.5, the yolk sac placenta is supplanted by the chorioallantoic (definitive) placenta, and around day 14.5 for the mouse, the CTB layer covering the villi becomes perforated, and maternal blood can now directly contact the outermost SYN layer.

    CREDIT: A. KITTERMAN/SCIENCE IMMUNOLOGY
  • Fig. 3 Mechanisms of maternal tolerance.

    The most abundant of the maternal immune cells present in the decidua are dNK cells, which are recruited by various factors released from the decidual stromal cells and placental trophoblasts. The release of uterine IL-15 promotes dNK maturation. The mature dNK cell promotes decidual remodeling and blastocyst implantation through the secretion of cytokines [including IFN-γ, VEGF, and tumor necrosis factor–α (TNFα)]. The release of IL-8 and CXCL10 by dNK also promotes EVT invasion. dNK cell cytotoxicity is controlled by the binding of HLA-G (expressed on the EVTs) to the inhibitory receptor KIR2DL4. Decidual macrophages prevent maternal intolerance by producing IDO, which hinders T cell activation, and phagocytosing apoptotic trophoblasts. Treg cells modulate the activities of both APCs and effector T (Teff) cells. The SYN also promotes maternal tolerance by secreting exosomes expressing TRAIL and FasL and by the lack of any MHC expression.

    CREDIT: A. KITTERMAN/SCIENCE IMMUNOLOGY
  • Fig. 4 Mechanisms of placental immune defense.

    The placenta has a number of innate immune mechanisms to protect the fetus from congenital infections of all types, including the expression of pattern recognition receptors such as Toll-like receptors (TLRs), the constitutive expression of type III IFNs (IFN-λ), and the release of antimicrobial peptides. Inoculation of placental trophoblasts with the parasite T. gondii induces the secretion of chemokines, including the potent T helper 2 and Treg cell chemoattractant CCL22, suggesting that parasite infection alters or signals to maternal-derived immune cells. Furthermore, SYN expression of the FcRn also suggests a protective role for maternal IgG within the fetal compartment through the development of passive immunity.

    CREDIT: A. KITTERMAN/SCIENCE IMMUNOLOGY

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