Pregnancy is a natural process that poses an immunological challenge because non-self fetus must be accepted. During the pregnancy period, the fetus as 'allograft' inherits maternal and also paternal ...antigens. For successful and term pregnancy, the fetus is tolerated and nurtured enjoying immune privileges that minimize the risk of being rejected by maternal immune system. Multiple mechanisms contribute to tolerate the semi-allogeneic fetus. Here, we summarize the recent progresses on how the maternal immune system actively collaborates to maintain the immune balance and maternal-fetal tolerance.
This comparative analysis of Scandinavian social democracies argues that the fate of socialist parties is decided, to a significant degree, by their own policies and reforms_not solely by the changes ...in social structure emphasized in previous studies. Combining quantitative analysis and historical case studies to demonstrate the electoral effects of party policy, Gosta Esping-Andersen formulates a theory that is applicable not only to Scandinavia but to Western Europe as a whole. In addition, he explains why the support basis of social democracy has deteriorated so much more in Denmark than in Sweden and Norway
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•Improved pregnancy outcomes were observed after TGF-β1 treatment following T. gondii infection.•TGF-β1 could down-regulate the expression of NKG2D/DAP10 of dNK cells induced by T. gondii ...infection.•TGF-β1 could down-regulate the ratio of killer subset of dNK cells induced by T. gondii infection.•TGF-β1 could decrease the cytotoxicity of dNK cells caused by T. gondii infection.
Our current aim was to investigate whether injection of TGF-β1 played an important role in improving abnormal pregnancy outcomes with T. gondii infection and how the TGF-β1 regulated. Results showed that TGF-β1 exhibited improved pregnancy outcomes induced by T. gondii infection. dNK cytotoxicity was increased with T. gondii infection while decreased with TGF-β1 treatment. dNK cytotoxicity related NKG2D/DAP10 expression, perforin, granzyme, IFN-γ and killer subsets were all increased with T. gondii infection while decreased after TGF-β1 treatment. In addition, anti-TGF-β1 antibodies could aggregate the cytotoxicity of dNK cells and the levels of molecules above. These results indicated that TGF-β1 treatment could improve the abnormal pregnancy outcomes with T. gondii infection by decreasing the cytotoxicity of dNK cells mediated by NKG2D/DAP10 pathway and killer subset. These results suggested that TGF-β1 might be a potential immunoprotective method for the treatment of abnormal pregnancy outcomes following T. gondii infection.
Toxoplasma gondii infection causes adverse pregnancy outcomes by affecting the expression of immunotolerant molecules in decidual immune cells. Galectin-9 (Gal-9) is widely expressed in decidual ...macrophages (dMphi) and is crucial for maintaining normal pregnancy by interacting with the immunomodulatory protein T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3). However, the effects of T. gondii infection on Gal-9 expression in dMphi, and the impact of altered Gal-9 expression levels on the maternal-fetal tolerance function of decidual natural killer (dNK) cells, are still unknown. Pregnancy outcomes of T. gondii-infected C57BL/6 and Lgals9.sup.-/- pregnant mice models were recorded. Expression of Gal-9, c-Jun N-terminal kinase (JNK), phosphorylated JNK (p-JNK), and Forkhead box protein O1 (FOXO1) was detected by western blotting, flow cytometry or immunofluorescence. The binding of FOXO1 to the promoter of Lgals9 was determined by chromatin immunoprecipitation-polymerase chain reaction (ChIP-PCR). The expression of extracellular signal-regulated kinase (ERK), phosphorylated ERK (p-ERK), cAMP-response element binding protein (CREB), phosphorylated CREB (p-CREB), T-box expressed in T cells (T-bet), interleukin 10 (IL-10), and interferon gamma (IFN-gamma) in dNK cells was assayed by western blotting. Toxoplasma gondii infection increased the expression of p-JNK and FOXO1 in dMphi, resulting in a reduction in Gal-9 due to the elevated binding of FOXO1 with Lgals9 promoter. Downregulation of Gal-9 enhanced the phosphorylation of ERK, inhibited the expression of p-CREB and IL-10, and promoted the expression of T-bet and IFN-gamma in dNK cells. In the mice model, knockout of Lgals9 aggravated adverse pregnancy outcomes caused by T. gondii infection during pregnancy. Toxoplasma gondii infection suppressed Gal-9 expression in dMphi by activating the JNK/FOXO1 signaling pathway, and reduction of Gal-9 contributed to dysfunction of dNK via Gal-9/Tim-3 interaction. This study provides new insights for the molecular mechanisms of the adverse pregnancy outcomes caused by T. gondii.
Natural killer (NK) cells are the predominant maternal uterine immune cell component, and they densely populate uterine mucosa to promote key changes in the post-ovulatory endometrium and in early ...pregnancy. It is broadly accepted that (a) immature, inactive endometrial NK (eNK) cells in the pre-ovulatory endometrium become activated and transition into decidual NK (dNK) cells in the secretory stage, peri-implantation endometrium, and continue to mature into early pregnancy; and (b) that secretory-stage and early pregnancy dNK cells promote uterine vascular growth and mediate trophoblast invasion, but do not exert their killing function. However, this may be an overly simplistic view. Evidence of specific dNK functional killer roles, as well as opposing effects of dNK cells on the uterine vasculature before and after conception, indicates the presence of a transitory secretory-stage dNK cell (s-dNK) phenotype with a unique angiodevelopmental profile during the peri-implantation period, that is that is functionally distinct from the angiomodulatory dNK cells that promote vessel destabilisation and vascular cell apoptosis to facilitate uterine vascular changes in early pregnancy. It is possible that abnormal activation and differentiation into the proposed transitory s-dNK phenotype may have implications in uterine pathologies ranging from infertility to cancer, as well as downstream effects on dNK cell differentiation in early pregnancy. Further, dysregulated transition into the angiomodulatory dNK phenotype in early pregnancy will likely have potential repercussions for adverse pregnancy outcomes, since impaired dNK function is associated with several obstetric complications. A comprehensive understanding of the uterine NK cell temporal differentiation pathway may therefore have important translational potential due to likely NK phenotypic functional implications in a range of reproductive, obstetric, and gynaecological pathologies.
Decidual natural killer (dNK) cells are the predominant lymphocytes accumulated at the maternal-fetal interface. Regulatory mechanism of dNK cells in preeclampsia, a gestational complication ...characterized by high blood pressure and increased proteinuria occurring after 20 weeks pregnancy, is not completely understood.
Multi-parameter flow cytometry is applied to investigate the phenotype and function of dNK cells freshly isolated from decidual samples or conditionally cultured by TGFb stimulation.
In preeclampsia, we documented elevated numbers of CD56+ CD3- dNK cells in close proximity to Foxp3+ regulatory T (Treg) cells within the decidua. In vitro experiments using dNK cells from early gestation showed that dNK activation (IFNG, IL-8 and CD107a) can be downregulated by Treg cells. The expression of these markers by dNK cells was significantly lower in preeclampsia. We also observed a positive correlation between the expression of dNK activation receptors (NKp30 and NKG2D) and the expression of IFNG in specific dNK subsets. TGFb levels are increased in the decidua of preeclamptic pregnancies. We analyzed co-expression of activation (IFNG/IL-8/CD107a) and angiogenic (VEGF) markers in dNK cells. TGFb treatment reduced while blockade of TGFb increased co-expression of these markers.
Our findings suggest that elevated decidual TGFb1 supresses the activation of specific subsets of dNK which in turn contributes to the uteroplacental pathology associated with the onset of preeclampsia.
Plasticity of NK cells in Cancer Corvino, Dillon; Kumar, Ananthi; Bald, Tobias
Frontiers in immunology,
05/2022, Volume:
13
Journal Article
Peer reviewed
Open access
Natural killer (NK) cells are crucial to various facets of human immunity and function through direct cytotoxicity or
orchestration of the broader immune response. NK cells exist across a wide range ...of functional and phenotypic identities. Murine and human studies have revealed that NK cells possess substantial plasticity and can alter their function and phenotype in response to external signals. NK cells also play a critical role in tumor immunity and form the basis for many emerging immunotherapeutic approaches. NK cells can directly target and lyse malignant cells with their inherent cytotoxic capabilities. In addition to direct targeting of malignant cells, certain subsets of NK cells can mediate antibody-dependent cellular cytotoxicity (ADCC) which is integral to some forms of immune checkpoint-blockade immunotherapy. Another important feature of various NK cell subsets is to co-ordinate anti-tumor immune responses by recruiting adaptive and innate leukocytes. However, given the diverse range of NK cell identities it is unsurprising that both pro-tumoral and anti-tumoral NK cell subsets have been described. Here, NK cell subsets have been shown to promote angiogenesis, drive inflammation and immune evasion in the tumor microenvironment. To date, the signals that drive tumor-infiltrating NK cells towards the acquisition of a pro- or anti-tumoral function are poorly understood. The notion of tumor microenvironment-driven NK cell plasticity has substantial implications for the development of NK-based immunotherapeutics. This review will highlight the current knowledge of NK cell plasticity pertaining to the tumor microenvironment. Additionally, this review will pose critical and relevant questions that need to be addressed by the field in coming years.
Miscarriage is a frustrating complication of pregnancy that is common among women of reproductive age. Insufficient decidualization which not only impairs embryo implantation but disturbs ...fetomaternal immune-tolerance, has been widely regarded as a major cause of miscarriage; however, the underlying mechanisms resulting in decidual impairment are largely unknown.
With informed consent, decidual tissue from patients with spontaneous abortion or normal pregnant women was collected to detect the expression profile of UCHL1. Human endometrial stromal cells (HESCs) were used to explore the roles of UCHL1 in decidualization and dNK modulation, as well as the mechanisms involved. C57/BL6 female mice (7-10 weeks old) were used to construct pregnancy model or artificially induced decidualization model to evaluate the effect of UCHL1 on mice decidualization and pregnancy outcome.
The Ubiquitin C-terminal hydrolase L1 (UCHL1), as a deubiquitinating enzyme, was significantly downregulated in decidua from patients with miscarriage, along with impaired decidualization and decreased dNKs. Blockage of UCHL1 led to insufficient decidualization and resultant decreased expression of cytokines CXCL12, IL-15, TGF-β which were critical for generation of decidual NK cells (dNKs), whereas UCHL1 overexpression enhanced decidualization accompanied by increase in dNKs. Mechanistically, the promotion of UCHL1 on decidualization was dependent on its deubiquitinating activity, and intervention of UCHL1 inhibited the activation of JAK2/STAT3 signaling pathway, resulting in aberrant decidualization and decreased production of cytokines associated with dNKs modulation. Furthermore, we found that inhibition of UCHL1 also disrupted the decidualization in mice and eventually caused adverse pregnancy outcome.
UCHL1 plays significant roles in decidualization and dNKs modulation during pregnancy in both humans and mice. Its deficiency indicates a poor pregnancy outcome due to defective decidualization, making UCHL1 a potential target for the diagnosis and treatment of miscarriage.
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