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There is crosstalk between decidual natural killer (dNK) cells and decidual dendritic cells (dDCs) that promotes tolerance of trophoblast cells carrying paternally derived antigens. In the present study, we report that infection of CD1c dDCs with Toxoplasma gondii enhanced gamma interferon (IFN-γ) production by dNK cells in co-culture. The enhancement of IFN-γ production was induced by cytokine IL-12 which increased obviously in co-culture of dDCs with dNK cells following T. gondii infection, and this enhancement largely abrogated when cells were cultured in the presence of an anti-IL-12 antibody. The expression of KIR2DL4 and NKG2D on dNK cells was increased after T. gondii infection, and higher expression of NKG2D was induced by co-cultured dDCs. Neutralization of IL-12 decreased NKG2D expression on dNK cells. Furthermore, dDCs with T. gondii infection increased the cytotoxicity of co-cultured dNK cells against K562 target cells, which was mediated by activating receptor of NKG2D. Thus, T. gondii infection of dDCs enhanced dNK cell IFN-γ production and NKG2D expression, and then led to increased cytotoxicity of dNK cells. The up-regulated dNK cell cytotoxicity at the maternal-fetal interface may contribute to abnormal pregnancy outcomes caused by T. gondii infection in early pregnancy. [ABSTRACT FROM AUTHOR]

Inhibitory receptors and activating receptor expressed on decidual natural killer (dNK) cells are generally believed to be important in abnormal pregnancy outcomes and induced adverse pregnancy. However, if Toxoplasma gondii (T. gondii) infection induced abnormal pregnancy was related to dNK cells changes is not clear. In this study, we used human dNK cells co-cultured with human extravillous cytotrophoblast (EVT) cells following YFP-Toxoplasma gondii (YFP-T. gondii) infection in vitro and established animal pregnant infection model. Levels of inhibitory receptors KIR2DL4 and ILT-2, their ligand HLA-G, and activating receptor NKG2D in human decidua, and NKG2A and its ligand Qa-1 and NKG2D in mice uterine were analyzed by real-time PCR and flow cytometry with levels of NKG2D significantly higher than those of KIR2DL4 and ILT-2 in vitro and in invo. The level of NKG2D was positively correlated with cytotoxic activity of dNK cells in vitro. Numbers of abnormal pregnancies were significantly greater in the infected group than in the control group. This result demonstrated that the increased NKG2D expression and imbalance between inhibitory receptors of dNK cells and HLA-G may contribute to abnormal pregnancy outcomes observed upon maternal infection with T. gondii. [ABSTRACT FROM AUTHOR]

Aims: Toinvestigate the immunoprotective effect of IL-10 on pregnancy in Toxoplasma gondii-infected C57BL/6 mice. Methods: Twenty-four pregnant mice were randomly divided into 3 equal groups, i.e. a control group (CG), an infected group (IG) and an infected group treated with IL-10 (IPTG). Each IPTG and IG mouse was infected with 400 T. gondii trophozoites on gestational day (GD) 8. Each IPTG mouse was injected with 1 μg recombinant mouse IL-10 via a tail vein on GD 10 and 12. The mice were sacrificed on day 7 postinfection. Qa-1 and NKG2A were analyzed in the placenta by flow cytometry and real-time PCR. IL-4, IL-10 and IFN-γ in the placenta supernatant were analyzed by ELISA. Statistical analysis was performed by one-way ANOVA. Results: IPTG mice showed a better mental state, had larger fetuses and placentas with a better blood supply and a lower resorption ratio compared to IG mice. NKG2A and Qa-1 were significantly increased in IPTG mice compared to IG mice (p < 0.05). IL-4 and IL-10 in IPTG placenta supernatant were increased (p < 0.05), but IFN-γ was decreased (p < 0.05) compared to IG placenta supernatant. The ratios of IFN-γ/IL-4 and IFN-γ/IL-10 were decreased in IPTG mice compared to IG mice (p < 0.05, p < 0.05). Conclusion: IL-10 plays an immunoprotective role and improves the pregnancy outcome of T. gondii-infected mice. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Toxoplasma gondii infection during pregnancy can result in adverse pregnancy outcomes. Previously, we have reported that these outcomes are associated with the impaired function of decidual Treg cells; however, the detailed mechanisms involved were unclear. It has been reported that the suppressive capacity of Treg cells is dependent on PD-1 expression. The present study explored the role of decidual PD-1+ Treg cell function in adverse pregnancy outcomes due to T. gondii infection. Toxoplasma gondii–infected pregnant mice were sacrificed on gestational day 14 and their pregnancy outcomes were observed. The expression of PD-1 on decidual Treg cells and expressions of Foxp3, CTLA-4, TGF-β, and IL-10 on decidual PD-1+ and PD-1− Treg cells were determined using flow cytometry. The results showed that the expression of PD-1 on decidual Treg cells was clearly higher in the T. gondii–infected mice than in the normal mice. Meanwhile, the expressions of Foxp3, CTLA-4, TGF-β, and IL-10 on decidual PD-1+ Treg cells were higher in the infected mice than in the normal mice. The expressions were higher in decidual PD1+ Treg cells than in PD-1− Treg cells in the infected mice. However, these expressions on PD-1− Treg cells did not significantly differ between the infected and normal mice. Nonetheless, the absolute percentages of decidual PD-1+ Treg cells decreased significantly in the infected mice compared with those in the normal mice. These results suggest that T. gondii infection mainly influences the function of decidual PD-1+ Treg cells, which would result in an insufficiently immunotolerant microenvironment and consequently in adverse pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Acute infection with Toxoplasma gondii (T. gondii) during pregnancy is associated with adverse outcomes. The mechanisms that cause this phenomenon are not clear. Regulatory T cells (Tregs) are involved in maternal tolerance, and here we observed a decrease in the absolute numbers of CTLA-4+ Tregs and PD-1+ Tregs in spleen and at the fetal-maternal interface in T. gondii-infected mice. Our results suggest that T. gondii induces apoptosis of Tregs. Additionally, we found that the expression of CTLA-4 and PD-1 on Tregs at fetal-maternal interface were higher than on spleen cells from normal pregnant mice. Therefore, we adoptively transferred Tregs from fetal-maternal interface or from spleens of normal pregnant mice into infected pregnant mice. Pregnancy outcomes were improved when Tregs were transferred from the fetal-maternal interface but not from the spleen. The mechanism appears to be through up-regulation of the number of CTLA-4+ Tregs and PD-1+ Tregs and correction of the imbalance between tolerant cytokines (IL-10, TGF-β) and inflammatory cytokines (IFN-γ). Our data indicate that Tregs at fetal-maternal interface express high levels of inhibitory molecules that play a vital immuno-protective role during pregnancy. [ABSTRACT FROM PUBLISHER]

The aim of this study were to demonstrate the effects of Yellow fluorescent protein- Toxoplasma gondii infection on the NK-92 cells co-cultured with BeWo cells in vitro and to verify the implications upon adverse pregnancy outcome. There are four groups including NK-92 cells infected or uninfected with T. gondii, and NK-92 cells co-cultured with BeWo cells in the presence or absent of T. gondii infection. Cells were observed by fluorescence microscope at 12, 24, 36, 48, and 60 h after infection. Levels of inhibitory receptors killer immunoglobulin-like receptor (KIR)2DL4 and ILT-2 expressed on NK-92 cells, and their common ligand HLA-G expressed on BeWo cells were measured by real-time PCR and flow cytometry in all groups. Levels of KIR2DL4, ILT-2 and HLA-G increased at 12, 24, 36, and 48 h, while decreased at 60 h in all T. gondii-infected groups compared with their parallel control groups, respectively. KIR2DL4 and ILT-2 expression in co-culture groups with infection were higher than those in infected NK-92 groups at 12, 24, 36, and 48 h, while there were no significant differences at 60 h. The expression of the two inhibitory receptors was correlated with HLA-G expression in infected co-culture groups. The changes of inhibitory receptors on NK-92 cells and their common ligand HLA-G on BeWo cells with T. gondii infection might contribute to the occurrence of adverse pregnancy outcome. [ABSTRACT FROM AUTHOR]

Objective: To investigate the changes of human decidual natural killer (dNK) cells cocultured with Toxoplasma gondii in vitro and to infer implications on pregnancy. Design: Case-control study. Setting: College and hospital. Patient(s): Decidual tissue was obtained from 85 patients undergoing voluntary abortion during the first trimester of gestation (6–12 weeks). Intervention(s): None. Main Outcome Measure(s): The dNK cells were isolated and infected with YFP-Toxoplasma gondii. Cells were observed by fluorescence and confocal microscopy. The CD56brightCD16−/CD56dimCD16+ dNK ratio, expression of KIR2DL4, ILT-2, and NKG2D on dNK cells were analyzed by flow cytometry and the cytotoxic activity of infected dNK cells were evaluated. Result(s): The CD56dimCD16+/CD56brightCD16− dNK ratio was significantly elevated at 12, 24, and 48 hours after YFP-T. gondii infection. Expression of KIR2DL4, ILT-2, and NKG2D were increased after infection, but NKG2D were significantly higher than those of KIR2DL4 and ILT-2. Both the CD56dimCD16+/CD56brightCD16− dNK ratio and NKG2D expression were correlated with dNK cytotoxic activity. Conclusion(s): Enhanced dNK cytotoxicity due to increased CD16 and NKG2D expression may contribute to abnormal pregnancy outcomes observed with maternal infection with T. gondii. [ABSTRACT FROM AUTHOR]