Decidual NK cells regulate key developmental processes at the human fetal-maternal interface

Hanna, Jacob; Goldman‐Wohl, Debra; Hamani, Yaron; Avraham, Inbal; Greenfield, Caryn; Natanson-Yaron, Shira; Prus, Diana; Cohen-Daniel, Leonor; Arnon, Tal I.; Manaster, Irit; Gazit, Roi; Yutkin, Vladimir; Benharroch, Daniel; Porgador, Angel; Keshet, Eli; Yagel, Simcha; Mandelboim, Ofer

doi:10.1038/nm1452

Cited by 1,462 publications

(1,531 citation statements)

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“…This immune switch, from a Th1 pro‐inflammatory environment to a Th2 anti‐inflammatory environment, is fundamental to the establishment of local maternal tolerance and is crucial for implantation. In this period, uterine natural killer (uNK) cells, together with macrophages and dendritic cells, increase in the endometrium and have a significant role in innate (Th2) immunity 30. Unlike peripheral natural killer cells, the uNK cells are not cytotoxic and their main biological functions are to produce immunotrophic and angiogenic cytokines.…”

Section: Discussionmentioning

confidence: 99%

Thin endometrium transcriptome analysis reveals a potential mechanism of implantation failure

Maekawa

Tanaka

Mihara

et al. 2017

Reprod Medicine & Biology

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AimAlthough a thin endometrium has been well recognized as a critical factor in implantation failure, little information is available regarding the molecular mechanisms. The present study investigated these mechanisms by using genome‐wide mRNA expression analysis.MethodsThin and normal endometrial tissue was obtained from a total of six women during the mid‐luteal phase of the menstrual cycle. The transcriptomes were analyzed with a microarray. Differentially expressed genes were classified according to Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways.ResultsThe study identified 318 up‐regulated genes and 322 down‐regulated genes in the thin endometrium, compared to the control endometrium. The GO and KEGG pathway analyses indicated that the thin endometrium possessed aberrantly activated immunity and natural killer cell cytotoxicity that was accompanied by an increased number of inflammatory cytokines, such as IFN‐γ. Various genes that were related to metabolism and anti‐oxidative stress were down‐regulated in the thin endometrium.ConclusionImplantation failure in the thin endometrium appears to be associated with an aberrantly activated inflammatory environment and aberrantly decreased response to oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Thin endometrium transcriptome analysis reveals a potential mechanism of implantation failure

Maekawa

Tanaka

Mihara

et al. 2017

Reprod Medicine & Biology

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“…Decidual natural killer cells are CD56 bright CD16 2 , and produce a variety of cytokines and growth factors that participate in spiral artery/tissue remodeling and placentation. 6 Decidual macrophages are alternatively activated to exert anti-inflammatory actions. These cells produce few reactive oxygen derivatives, but do produce IL-10 and IL1-R antagonist.…”

Section: Introductionmentioning

confidence: 99%

The CXCL12/CXCR4 axis is involved in the maintenance of Th2 bias at the maternal/fetal interface in early human pregnancy

Piao

Zhu

et al. 2012

Cell Mol Immunol

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The regulatory mechanism of Th2 bias at the maternal/fetal interface remains unclear. In this study, we characterized cytokine production in decidual stromal cells (DSCs), decidual immune cells (DICs) and embryo-derived trophoblast cells, and investigated the regulation of CXCL12/CXCR4 interaction on Th2 bias at the maternal/fetal interface in early human pregnancy. We found differential production of Th1-type and Th2-type cytokines by trophoblasts, DSCs and DICs. The secretion of these cytokines varied in different cell cocultures, conduced to Th2 bias. Flow cytometry showed that coculture of trophoblasts with DSCs and DICs significantly increased IL-4 and IL-10 production in trophoblasts, and IL-10 production in DSCs. However, the coculture of trophoblasts with DSCs and DICs significantly increased interferon (IFN)-c expression in DSCs, and tumor-necrosis factor (TNF)-a expression in DICs. No change was seen in Th1-type cytokine production in trophoblasts, and in Th2-type cytokine production in DICs in all cocultures. Furthermore, pre-treatment with anti-CXCR4 neutralizing antibody upregulated the production of the Th1-type cytokines IFN-c and TNF-a, and downregulated the production of the Th2-type cytokines IL-4 and IL-10, in trophoblasts, DSCs, DICs or their cocultures. Interestingly, rhCXCL12 inhibited production of the Th1-type cytokine TNF-a and enhanced the expression of the Th2-type cytokines such as IL-4 and IL-10 in DICs; this effect was abrogated by anti-CXCR4 antibody. Our present study has elucidated the individual contributions of component cells to the shaping of Th2 bias, and uncovered a complicated cross-talk via the CXCL12/CXCR4 signal at the maternal/fetal interface in early human pregnancy.

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“…14,[17][18][19][20] Evidence also suggests the emergence of KIR to fulfill important roles during pregnancy [21][22][23] in which it has been shown that they influence the role of uterine NK cell in vascular remodeling during fetal trophoblast cell invasion of the deciduas. 24 As a likely consequence of these selective pressures, KIR diversity at the genetic, phenotypic and functional levels is immense. For instance, polygenicity gives rise to a vast array of different KIR haplotypes in human populations.…”

Section: Introductionmentioning

confidence: 99%

Receptor systems controlling natural killer cell function are genetically stratified in Europe

et al. 2009

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Natural killer (NK) cells are components of the innate immune system that function in identifying and destroying aberrant or pathogen-infected cells. These functions are largely controlled by killer cell immunoglobulin-like receptors (KIRs). KIRs inhibit and activate NK cell functions through interactions with their ligands, epitopes encoded by human leukocyte antigen (HLA) class I genes (HLA-C1, C2 and Bw4). Genes that encode KIR and their HLA ligands vary in frequency across human populations. Here, we characterize two Irish populations for KIR and HLA and determine the spatial distribution of functionally important KIR:HLA systems in Europe, a region known for its considerable underlying genetic stratification. We find that Southern Europe is a region characterized by higher frequencies of activatory KIR and strong inhibitory HLA ligand systems (2DL1:HLA-C2 and 3DL1:Bw4). A lower frequency of activatory KIR and the predominance of a comparatively weaker inhibitory ligand system (2DL3:HLA-C1) are observed northwards. Despite contrasting KIR:HLA systems in Northern and Southern Europe, there is a clear balance between inhibitory and activatory repertoires, and their ligands in both regions. These findings show 'functional stratification' of the epistatic KIR:HLA receptor system in Europe, the presence of which will likely affect NK cell-mediated immunity across different populations.

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Decidual NK cells regulate key developmental processes at the human fetal-maternal interface

Cited by 1,462 publications

References 47 publications

Thin endometrium transcriptome analysis reveals a potential mechanism of implantation failure

Thin endometrium transcriptome analysis reveals a potential mechanism of implantation failure

The CXCL12/CXCR4 axis is involved in the maintenance of Th2 bias at the maternal/fetal interface in early human pregnancy

Receptor systems controlling natural killer cell function are genetically stratified in Europe

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