ORIGINAL ARTICLE: Urocortin Increases IL‐4 and IL‐10 Secretion and Reverses LPS‐induced TNF‐α Release from Human Trophoblast Primary Cells

Zhu

et al. 2012

Cell Mol Immunol

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.

Section: Discussionmentioning

confidence: 99%

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

Zhu

et al. 2012

Cell Mol Immunol

“…Trophoblasts can influence the immune system during pregnancy by expressing soluble and cell surface molecules, such as HLA-G (16,17), IDO (26), and noninflammatory cytokines (27,15). These molecules can limit proliferation and activation of T cells, APCs, and NK cells in deciduas.…”

Section: Discussionmentioning

confidence: 99%

Embryonic Trophoblasts Induce Decidual Regulatory T Cell Differentiation and Maternal–Fetal Tolerance through Thymic Stromal Lymphopoietin Instructing Dendritic Cells

Guo

The Journal of Immunology

et al. 2014

117

Physiological pregnancy requires the maternal immune system to recognize and tolerate embryonic Ags. Although multiple mechanisms have been proposed, it is not yet clear how the fetus evades the maternal immune system. In this article, we demonstrate that trophoblast-derived thymic stromal lymphopoietin (TSLP) instructs decidual CD11c+ dendritic cells (dDCs)with increased costimulatory molecules; MHC class II; and Th2/3-type, but not Th1-type, cytokines. TSLP-activated dDCs induce proliferation and differentiation of decidual CD4+CD25− T cells into CD4+CD25+FOXP3+ regulatory T cells (Tregs) through TGF-β1. TSLP-activated dDC–induced Tregs display immunosuppressive features and express Th2-type cytokines. In addition, decidual CD4+CD25+FOXP3+ Tregs promote invasiveness and HLA-G expression of trophoblasts, resulting in preferential production of Th2 cytokines and reduced cytotoxicity in decidual CD56brightCD16− NK cells. Of interest, decreased TSLP expression and reduced numbers of Tregs were observed at the maternal–fetal interface during miscarriage. Our study identifies a novel feedback loop between embryo-derived trophoblasts and maternal decidual leukocytes, which induces a tolerogenic immune response to ensure a successful pregnancy.

“…39,40 Both proand anti-inflammatory cytokines in trophoblasts were downregulated in spontaneously aborted pregnancies. 41 Trophoblasts produce cytokines, such as TSLP, to instruct decidual dendritic cells and to induce a TH2 bias at the maternal/fetal interface.…”

Section: Discussionmentioning

confidence: 99%

CD56brightCD25+ NK cells are preferentially recruited to the maternal/fetal interface in early human pregnancy

et al. 2014

Cell Mol Immunol

Decidual natural killer (dNK) cells are believed to be critical for maintaining maternal/fetal tolerance and regulating placental vascular remodeling based upon their abundance and unique phenotype during early pregnancy. However, the mechanism for how the dNK cells play such important roles in successful pregnancy remains undefined. Here, we identified a subtype of dNK cells characterized as having a CD3 2 CD56 bright CD25 1 phenotype. We found that CD56 bright CD25 1 NK cells preferentially localize to the maternal/fetal interface during early human pregnancy. CD25 1 dNK cells account for approximately 75% of CD25-expressing decidual immune cells (DICs). However, less than 5% of CD25-positive peripheral blood mononuclear cells are CD25 1 NK cells. Furthermore, CD25 1 and CD25 2 dNK cells exhibit distinct phenotypes: CD25 1 dNK cells display a more activated phenotype and greater cytokine-secreting capacity. Interestingly, coculture of peripheral NK (pNK) cells with primary trophoblasts upregulates the percentage of CD25-expressing pNK cells, resulting in increased expression of activation markers and cytokine production by pNK cells. In addition, we demonstrated that the CXCL12/CXCR4 axis is crucial for the recruitment of CD25 1 dNK cells and contributes to the accumulation of CD3 2 CD56 bright CD25 1 dNK cells at the maternal/fetal interface. Thus, our data reveal that the crosstalk between trophoblasts and pNK cells leads to the accumulation of CD3 2 CD56 bright CD25 1 dNK cells, which exert a regulating effect at the maternal/fetal interface.