Maternal Decidual Macrophages Inhibit NK Cell Killing of Invasive Cytotrophoblasts During Human Pregnancy

Biology of Reproduction (Impact Factor: 3.32). 04/2013; 88(6). DOI: 10.1095/biolreprod.112.099465
Source: PubMed

ABSTRACT Human pregnancy is an immunological paradox. Semi-allogeneic (fetal) placental cells (extravillous cytotrophoblasts; CTBs) invade the uterine lining (decidua), which contains a unique decidual Natural Killer (dNK) cell population, identified by the cell-surface phenotype CD56(bright)CD16(-)CD3(-) and CD14(+) CD206(+) macrophages (dMac). Previous reports suggested that human dNK cells are not a threat to the feto-placental unit because they are anergic. In contrast, here we showed that purified and exogenously stimulated dNK cells are capable killers of cellular targets, including semi-allogeneic CTBs. However, dMacs in the decidual leukocyte (DL) population restrained dNK killing through a Transforming Growth Factor (TGF)-β1-dependent mechanism. Our findings support a new model whereby dNK cells, capable of killing CTBs, are prevented from doing so by neighboring macrophages, thus protecting the fetal cells from NK cell attack. We speculate that this mechanism would inhibit dNK cell-mediated killing, even in conditions where high levels of cytokines may stimulate dNK cells, which could pose a threat to the developing placenta.

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    • "Embryo implantation and trophoblast invasion create a pro-inflammatory environment leading to the recruitment of immune cells that mediate maternal tolerance to the semi-allogeneic embryo [5,10]. Decidual macrophages are the second most abundant immune cell population at the implantation site, comprising 20-30% of immune cells in the uterine decidua [4,11,12]. "
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    ABSTRACT: Background Angiogenesis and macrophage recruitment to the uterus are key features of uterine decidualization; the progesterone-mediated uterine changes that allow for embryo implantation and initiation of pregnancy. In the current study, we characterized the expression of vascular endothelial growth factor receptor-1 (VEGFR-1) in macrophages and endothelial cells of the peri-implantation uterus and determined if VEGFR-1 function is required for decidual angiogenesis, macrophage recruitment, and/or the establishment of pregnancy. Methods Expression of VEGFR-1 in uterine endothelial cells and macrophages was determined with immunohistochemistry. To assess the effect of continuous VEGFR-1 blockade, adult female mice were given VEGFR-1 blocking antibody, MF-1, every 3 days for 18 days. After 6 doses, females were mated and a final dose of MF-1 was given on embryonic day 3.5. Endothelial cells and macrophages were quantified on embryonic day 7.5. Pregnancy was analyzed on embryonic days 7.5 and 10.5. Results F4/80+ macrophages are observed throughout the stroma and are abundant adjacent to the endometrial lumen and glands prior to embryo implantation and scatter throughout the decidua post implantation. VEGFR-1 expression is restricted to the uterine endothelial cells. F4/80+ macrophages were often found adjacent to VEGFR-1+ endothelial cells in the primary decidual zone. Continuous VEGFR-1 blockade correlates with a significant reduction in decidual vascular and macrophage density, but does not affect embryo implantation or maintenance of pregnancy up to embryonic day 10.5. Conclusions We found that VEGFR-1 functions in both decidual angiogenesis and macrophage recruitment to the implantation site during pregnancy. VEGFR-1 is expressed by endothelial cells, however blocking VEGFR-1 function in endothelial cells results in reduced macrophage recruitment to the uterus. VEGFR-1 blockade did not compromise the establishment and/or maintenance of pregnancy.
    Vascular Cell 08/2014; 6(1):16. DOI:10.1186/2045-824X-6-16
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    ABSTRACT: Survival of the allogeneic embryo in the uterus depends on the maintenance of immune tolerance at the maternal-fetal interface. The pregnant uterus is replete with activated maternal immune cells. How this immune tolerance is acquired and maintained has been a topic of intense investigation. The key immune cells that predominantly populate the pregnant uterus are natural killer (NK) cells. In normal pregnancy, these cells are not killers, but rather provide a microenvironment that is pregnancy compatible and supports healthy placentation. In placental mammals, an array of highly orchestrated immune elements to support successful pregnancy outcome has been incorporated. This includes active cooperation between maternal immune cells, particularly NK cells, and trophoblast cells. This intricate process is required for placentation, immune regulation and to remodel the blood supply to the fetus. During the past decade, various types of maternal immune cells have been thought to be involved in cross-talk with trophoblasts and in programming immune tolerance. Regulatory T cells (Tregs) have attracted a great deal of attention in promoting implantation and immune tolerance beyond implantation. However, what has not been fully addressed is how this immune-trophoblast axis breaks down during adverse pregnancy outcomes, particularly early pregnancy loss, and in response to unscheduled inflammation. Intense research efforts have begun to shed light on the roles of NK cells and Tregs in early pregnancy loss, although much remains to be unraveled in order to fully characterize the mechanisms underlying their detrimental activity. An increased understanding of host-environment interactions that lead to the cytotoxic phenotype of these otherwise pregnancy compatible maternal immune cells is important for prediction, prevention and treatment of pregnancy maladies, particularly recurrent pregnancy loss. In this review, we discuss relevant information from experimental and human models that may explain the pregnancy disrupting roles of these pivotal sentinel cells at the maternal-fetal interface.
    The International Journal of Developmental Biology 07/2014; 58(2-3-4):219-229. DOI:10.1387/ijdb.140109ss · 1.90 Impact Factor
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    ABSTRACT: Abstract Natural killer (NK) cells that provide first-line innate immune reactions against virus-infected and tumor cells have different roles in different body sites and in different stages. From the beginning of life, NK cells participate in many aspects of development, especially in a successful pregnancy and a healthy neonatal stage. This article reviews recent advances regarding the role of NK cells in implantation, placentation and immune tolerance during pregnancy as well as in the neonatal immune defense. The interactions between NK cells and other immune cells in each developmental stage are discussed.
    Journal of Perinatal Medicine 04/2014; 43(1). DOI:10.1515/jpm-2013-0244 · 1.36 Impact Factor
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