Chemokine Gene Silencing in Decidual Stromal Cells Limits T Cell Access to the Maternal-Fetal Interface

Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Science (Impact Factor: 33.61). 06/2012; 336(6086):1317-21. DOI: 10.1126/science.1220030
Source: PubMed

ABSTRACT The chemokine-mediated recruitment of effector T cells to sites of inflammation is a central feature of the immune response. The extent to which chemokine expression levels are limited by the intrinsic developmental characteristics of a tissue has remained unexplored. We show in mice that effector T cells cannot accumulate within the decidua, the specialized stromal tissue encapsulating the fetus and placenta. Impaired accumulation was in part attributable to the epigenetic silencing of key T cell-attracting inflammatory chemokine genes in decidual stromal cells, as evidenced by promoter accrual of repressive histone marks. These findings give insight into mechanisms of fetomaternal immune tolerance, as well as reveal the epigenetic modification of tissue stromal cells as a modality for limiting effector T cell trafficking.

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    • "Stromal and immune cells present at the fetal-maternal interface are suspected to play many important roles in the maintenance and regulation of pregnancy [2], [12]–[15]. "
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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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    • "However, information about immune cell dynamics at the maternal–fetal interface remains limited, while abundant in other models such as cancer, infection, or inflammation [reviewed in Ref. (90)]. T-cells are relatively rare in the uterus of both pregnant and non-pregnant human beings and mice (91, 92). However, despite their paucity, Tregs are critical for normal pregnancy. "
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    ABSTRACT: In this review, we first revisit the original concept of "suppressor T-cells" in pregnancy, put it in a historical perspective, and then highlight the main data that licensed its resurrection and revision into the concept of "regulatory T-cells" (Tregs) in pregnancy. We review the evidence for a major role of Tregs in murine and human pregnancy and discuss Treg interactions with dendritic and uterine natural killer cells, other players of maternal-fetal tolerance. Finally, we highlight what we consider as the most important questions in the field.
    Frontiers in Immunology 08/2014; 5:389. DOI:10.3389/fimmu.2014.00389
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    • "Moreover, we propose that at the earliest phases of an infection, trophoblast cells would selectively modulate chemokines and their receptor expression as one of the first steps to control leukocyte trafficking to avoid potential tissue damage. In this sense, Nancy et al. recently reported that decidual stromal cells impaired the accumulation of maternal effector T cells within the decidua by the epigenetic silencing of T cell-attracting inflammatory chemokines genes through repressive histone marks [43]. "
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    ABSTRACT: Macrophages at the maternal-placental interface coordinate opposite demands under the control of trophoblast cells such as the response against pathogens on one hand, and apoptotic cell clearance and wound healing with the production of suppressor cytokines. Here, we investigated whether trophoblast cells induce maternal monocyte activation towards an alternative activated macrophage profile and whether bacterial or viral stimuli modulate their migratory properties. We used an in vitro model of the maternal-placental interface represented by co-cultures of CD14+ cells isolated from fertile women with first trimester trophoblast cell line (Swan-71 cells) in the presence or absence of pathogen associated molecular pattern (PAMP) stimuli lipopolysaccharide (LPS), peptidoglycan (PGN) or poly [I:C]). Maternal CD14+ cells showed increased CD16 and CD39 expression, both markers associated to an alternative activation profile, with no changes in CD80 expression after trophoblast cell interaction. These changes were accompanied by increased IL-10 and decreased IL-12 production by CD14+ cells. After stimulation with LPS, PGN or poly [I:C], monocytes co-cultured with trophoblast cells had lower production of TNF-α and IL-1β compared with non co-cultured monocytes. Interestingly, monocyte migration towards trophoblast cells was prevented in the presence of LPS or PGN but not after 24h of stimulation with poly [I:C]. LPS or PGN also decreased CCR5, CXCL-8 and CCL5 expression. Finally, trophoblast cells co-cultured with monocytes in the presence of pathological stimuli failed to increase chemokine expression, indicating a bidirectional effect. In conclusion, trophoblast might 'instruct' maternal monocytes to express an alternative activation profile and restrain their early recruitment under pathological threats as one of the first strategies to avoid potential tissue damage at the maternal-placental interface.
    PLoS ONE 05/2014; 9(5):e97147. DOI:10.1371/journal.pone.0097147 · 3.23 Impact Factor
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