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

Co, Elizabeth Chava; Gormley, Matthew; Kapidzic, Mirhan; Rosen, David B.; Scott, Jake; Stolp, Haley; McMaster, Michael; Lanier, Lewis L.; Bárcena, Alicia; Fisher, Susan J.

doi:10.1095/biolreprod.112.099465

Cited by 114 publications

(82 citation statements)

References 68 publications

(90 reference statements)

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“…For example, decidual macrophages are able to inhibit NK cell cytotoxicity (Co et al, 2013), to suppress T cell proliferation and activation (Mizuno et al, 1994;Sayama et al, 2013) and to induce Treg cells (Vacca et al, 2010;Hsu et al, 2012), which our results further support. Also decidual stromal cells have been shown to contribute to limited T cell activation and induction of Treg cells (Nagamatsu et al, 2009;Erkers et al, 2013).…”

Section: Macrophages Th Cells and Treg Cellssupporting

confidence: 83%

“…Another observation indicating an immune regulatory function of decidual macrophages was their role in the clearance of apoptotic cells (Mor and Abrahams, 2003). It is only recently that the function of human decidual macrophages has been studied in more detail, and several reports now suggest that decidual macrophages influence the function of both decidual NK cells and T cells (Vacca et al, 2010;Co et al, 2013;Sayama et al, 2013). The function of decidual macrophages is likely controlled by epigenetic mechanisms; in particular, genes encoding M1-associated factors (for instance IL-1β and the IL-12 receptor β2 subunit) are hypermethylated, while genes encoding M2-associated factors (for instance A2M and IL-10) are hypomethylated, suggesting a predisposition towards an immune regulatory phenotype .…”

Section: Phenotype and Function Of Decidual Macrophagesmentioning

confidence: 99%

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Immune regulation at the fetal‐maternal interface with focus on decidual macrophages

Svensson‐Arvelund¹

2015

Linköping University Medical Dissertations

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A successful pregnancy requires that the maternal immune system adapts to tolerate the semi-allogeneic fetal-placental unit. This adaptation mainly occurs locally, i.e. at the fetal-maternal interface, where fetal-derived tissues come into close contact with maternal cells in the uterine endometrium (called decidua during pregnancy). decidual macrophages preferentially secreted the monocyte-and Treg cell-associated chemokines CCL2 and CCL18, while Th1-, Th2-and Th17-related chemokines were produced at low levels. These results suggest that decidual macrophages contribute to create the unique decidual cell composition and a tolerogenic immune environment that is compatible with fetal development. Further, by comparing decidual macrophages with different in vitro macrophage subsets, we showed that M-CSF and

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Section: Macrophages Th Cells and Treg Cellssupporting

confidence: 83%

Section: Phenotype and Function Of Decidual Macrophagesmentioning

confidence: 99%

Immune regulation at the fetal‐maternal interface with focus on decidual macrophages

Svensson‐Arvelund¹

2015

Linköping University Medical Dissertations

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“…The Fisher's group proposed that decidual Mws can also protect fetal cells (i.e., trophoblast cells) against the death-inducing activity of IFN-c-producing uterine NK cells through a transforming growth factor beta 1-dependent mechanism. 64 IFN-c-mediated activation of gene transcription occurs primarily through the transcription factor Stat1. 15 Once Stat1 is phosphorylated by Jak1 and Jak2, Stat1 homodimerizes, translocates to the nucleus, and activates the transcription of multiple genes that contain an IFN-c-activating sequence in their promoters.…”

Section: Discussionmentioning

confidence: 99%

The activating effect of IFN-γ on monocytes/macrophages is regulated by the LIF–trophoblast–IL-10 axis via Stat1 inhibition and Stat3 activation

et al. 2014

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Interferon gamma (IFN-c) and leukemia inhibitory factor (LIF) are key gestational factors that may differentially affect leukocyte function during gestation. Because IFN-c induces a pro-inflammatory phenotype in macrophages and because trophoblast cells are principal targets of LIF in the placenta, we investigated whether and how soluble factors from trophoblast cells regulate the effects of IFN-c on macrophage activation. IFN-c reduces macrophage motility, but enhances Stat1 activation, pro-inflammatory gene expression and cytotoxic functions. Soluble factors from villous cytotrophoblasts (vCT1LIF cells) and BeWo cells (BW/ST1LIF cells) that were differentiated in the presence of LIF inhibit macrophage Stat1 activation but inversely sustain Stat3 activation in response to IFN-c. vCT1LIF cells produce soluble factors that induce Stat3 activation; this effect is partially abrogated in the presence of neutralizing anti-interleukin 10 (IL-10) antibodies. Moreover, soluble factors from BW/ST1LIF cells reduce cell proliferation but enhance the migratory responses of monocytes. In addition, these factors reverse the inhibitory effect of IFN-c on monocyte/macrophage motility. BW/ST1LIF cells also generate IFN-c-activated macrophages with enhanced IL-10 expression, but reduced tumor-necrosis factor alpha (TNF-a), CD14 and CD40 expression as well as impaired cytotoxic function. Additional assays performed in the presence of neutralizing anti-IL-10 antibodies and exogenous IL-10 demonstrate that reduced macrophage cytotoxicity and proliferation, but increased cell motility result from the ability of trophoblast IL-10 to sustain Stat3 activation and suppress IFN-c-induced Stat1 activation. These in vitro studies are the first to describe the regulatory role of the LIF-trophoblast-IL-10 axis in the process of macrophage activation in response to pro-inflammatory cytokines.

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“…Furthermore, the presence of high proportions of other decidual immune cells, such as macrophages and regulatory T cells, may further influence the capacity of dNK to respond to healthy or virus-infected EVT (31). Decidual macrophages in particular have been shown to restrain killing of the semiallogeneic cytotrophoblasts by dNK by a TGF-β-dependent mechanism (48). Further investigation is needed to determine if there are conditions under which dNK are able to kill infected EVT.…”

Section: Kir2ds1 Expression On Dnk Correlated With a Relatively High mentioning

confidence: 99%

Expression of KIR2DS1 by decidual natural killer cells increases their ability to control placental HCMV infection

Crespo

Strominger

Tilburgs

2016

Proc. Natl. Acad. Sci. U.S.A.

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The combination of the activating killer cell Ig-like receptor 2DS1 (KIR2DS1) expressed by maternal decidual natural killer cells (dNK) and the presence of its ligand, the HLA-C allotype HLA-C2, expressed by fetal trophoblasts, reduces the risk of developing pregnancy complications. However, no molecular or cellular mechanism explains this genetic correlation. Here we demonstrate that KIR2DS1+ dNK acquired higher cytotoxic function than KIR2DS1− dNK when exposed to human cytomegalovirus (HCMV)-infected decidual stromal cells (DSC), particularly when DSCs express HLA-C2. Furthermore, dNK were unable to degranulate or secrete cytokines in response to HCMV-infected primary fetal extravillous trophoblasts. This emphasizes the immunological challenge to clear placental viral infections within the immune-privileged placenta. Activation of dNK through KIR2DS1/ HLA-C2 interaction increases their ability to respond to placental HCMV infection and may limit subsequent virus-induced placental pathology. This mechanism is directly related to how KIR2DS1 expressed by dNK reduces development of severe pregnancy complications such as miscarriages and preterm delivery.human | HLA-C | trophoblast | pregnancy | immune tolerance

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

Cited by 114 publications

References 68 publications

Immune regulation at the fetal‐maternal interface with focus on decidual macrophages

Immune regulation at the fetal‐maternal interface with focus on decidual macrophages

The activating effect of IFN-γ on monocytes/macrophages is regulated by the LIF–trophoblast–IL-10 axis via Stat1 inhibition and Stat3 activation

Expression of KIR2DS1 by decidual natural killer cells increases their ability to control placental HCMV infection

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