Flip a coin: cell senescence at the maternal-fetal interface†.

During pregnancy, cell senescence at the maternal-fetal interface is required for maternal well-being, placental development, and fetal growth. However, recent reports have shown that aberrant cell senescence is associated with multiple pregnancy-associated abnormalities, such as preeclampsia, fetal growth restrictions, recurrent pregnancy loss, and preterm birth. Therefore, the role and impact of cell senescence during pregnancy requires further comprehension. In this review, we discuss the principal role of cell senescence at the maternal-fetal interface, emphasizing its "bright side" during decidualization, placentation, and parturition. In addition, we highlight the impact of its deregulation and how this "dark side" promotes pregnancy-associated abnormalities. Furthermore, we discuss novel and less invasive therapeutic practices associated with the modulation of cell senescence during pregnancy.

Age-related changes in CD4+ T and NK cell compartments may contribute to the occurrence of pregnancy loss in advanced maternal age.

A recent study characterized novel immune cell subsets (T, NK, and γδ T cell subsets) related to recurrent pregnancy loss (RPL). This study aims to assess whether these RPL-related immune cell subsets are affected by aging. The percentages of peripheral blood immunes cells from nulligravida women (NGW), women with a history of normal pregnancy (NP), and women with a history of pregnancy loss (PL) were detected by flow cytometry. The correlations between maternal age and cell percentages were assessed. We found a significant positive correlation between PL and maternal age. The percentages of effector memory CD4+ T (CD3+ CD4+ CD45RA¯ CCR7¯), terminally differentiated CD4+ T (CD3+ CD4+ CD45RA+ CCR7¯), and mature NK cells (CD3¯ CD56+lo) significantly increased with maternal age. A significant decrease in the percentage of Naïve CD4+ T cells (CD3+ CD4+ CD45RA+ CCR7+) with age was observed in women from the NP group. Women aged 35 or older had significantly higher percentages of effector memory CD4+ T cells, terminally differentiated CD4+ T cells, and mature NK cells than younger women. Maternal age positively correlates with terminally differentiated CD4+ T, effector memory CD4+ T, and mature NK cell percentages. In contrast, an inverse correlation was observed between Naïve CD4+ T cell and age among women from the NP group. Our findings indicate that age-related CD4+ T and NK cell dysregulation might be involved in the pathogenesis of PL in women with advanced maternal age. The underlying mechanism needs further investigation.

Altered vitamin D metabolism is involved in the dysregulation of γδT cell function and their crosstalk with trophoblasts in recurrent pregnancy loss.

BACKGROUND: Recurrent pregnancy loss (RPL) is a common disease characterized by immune dysfunction and vitamin D deficiency. This study aimed to investigate vitamin D metabolism and γδT cell phenotypes at the maternal-fetal interface in women with early normal pregnancy (NP) and RPL and to determine the effects of vitamin D on the functions of γδT cells and their crosstalk with trophoblasts. METHODS: The levels of 25-(OH)VD3 , the expression of vitamin D metabolic enzymes in the villi, and the proportion of γδT cells in the decidua were detected in women with NP and RPL. After treatment with different concentrations of vitamin D, the mRNA expression of the vitamin D receptor (VDR), cytokines, and transcription factors were detected in Vδ2+ γδT cells. In addition, the proliferation, migration, and invasion of HTR-8/SVneo trophoblasts were determined by coculturing them with vitamin D-treated Vδ2+ γδT cells and their supernatants. RESULTS: In women with RPL, the level of 25-(OH)VD3 in the villi was increased; however, that of CYP27B1 (enzyme converting 25-(OH)VD3 into 1,25-(OH)2 VD3 ) was decreased. In addition, the proportion of Vδ2+ γδT cells increased, whereas that of Foxp3+ Vδ2+ γδT cells decreased in the decidua of women with RPL. An in vitro study showed that vitamin D increased the expression of VDR mRNA and Foxp3, but decreased the expression of IFN-γ mRNA, in Vδ2+ γδT cells. Finally, vitamin D-treated Vδ2+ γδT cells promoted trophoblast migration and invasion. CONCLUSIONS: Abnormal vitamin D metabolism and γδT cell proportions were present at the maternal-fetal interface in women with RPL. Under normal pregnancy conditions, vitamin D can induce the differentiation of decidual Vδ2+ γδT cells toward an anti-inflammatory phenotype (Treg-like γδT cells) and modulate the crosstalk between Vδ2+ γδT cells and trophoblasts.

Leukocyte immunoglobulin-like receptor subfamily B: A novel immune checkpoint molecule at the maternal-fetal interface.

Due to their crucial roles in embryo implantation, maternal-fetal tolerance induction, and pregnancy progression, immune checkpoint molecules (ICMs), such as programmed cell death-1, cytotoxic T-lymphocyte antigen 4, and T cell immunoglobulin mucin 3, are considered potential targets for clinical intervention in pregnancy complications. Despite the considerable progress on these molecules, our understanding of ICMs at the maternal-fetal interface is still limited. Identification of alternative and novel ICMs and the combination of multiple ICMs is urgently needed for deeply understanding the mechanism of maternal-fetal tolerance and to discover the causes of pregnancy complications. Leukocyte immunoglobulin-like receptor subfamily B (LILRB) is a novel class of ICMs with strong negative regulatory effects on the immune response. Recent studies have revealed that LILRB is enriched in decidual immune cells and stromal cells at the maternal-fetal interface, which can modulate the biological behavior of immune cells and promote immune tolerance. In this review, we introduce the structural features, expression profiles, ligands, and orthologs of LILRB. In addition, the potential mechanisms and functions mediated by LILRB for sustaining the maternal-fetal tolerance microenvironment, remodeling the uterine spiral artery, and induction of pregnancy immune memory are summarized. We have also provided new suggestions for further understanding the roles of LILRB and potential therapeutic strategies for pregnancy-related diseases.

IL-10: A bridge between immune cells and metabolism during pregnancy.

Energy metabolism plays a crucial role in the immune system. In addition to providing vital energy for cell growth, reproduction and other cell activities, the metabolism of nutrients such as glucose and lipids also have significant effects on cell function through metabolites, metabolic enzymes, and changing metabolic status. Interleukin-10 (IL-10), as a pleiotropic regulator, can be secreted by a diverse set of cells and can also participate in regulating the functions of various cells, thereby playing an essential role in the formation and maintenance of immune tolerance in pregnancy. Studies on the regulatory effects and mechanisms of IL-10 on immune cells are extensive; however, research from a metabolic perspective is relatively negligible. Here, we have discussed old and new data on the relationship between IL-10 and metabolism. The data show that alterations in cellular metabolism and specific metabolites regulate IL-10 production of immune cells. Moreover, IL-10 regulates immune cell phenotypes and functions by modulating oxidative phosphorylation and glycolysis. This review summarizes some earlier observations regarding IL-10 and its relationship with immune cells in pregnancy, and also presents recent research on the link between IL-10 and metabolism, highlighting the potential relationship between IL-10, immune cells, and energy metabolism during pregnancy.

Human leukocyte antigens: the unique expression in trophoblasts and their crosstalk with local immune cells.

Trophoblasts differentiate and form the placenta during pregnancy in a complex and finely orchestrated process, which is dependent on the establishment of maternal-fetal immune tolerance and the proper function of trophoblasts. Trophoblasts express HLA-C and non-classical HLA-Ib molecules (HLA-E, HLA-F, and HLA-G). Numerous studies have shown that the unique expression pattern of the HLA molecules is closely linked to the successful acceptance of allogeneic fetus by the mother during pregnancy. However, some controversies still exist concerning the exact expression and recognition patterns of HLA molecules in different trophoblast subpopulations and cell lines. Thus, we summarize three types of trophoblast subpopulations as well as the common trophoblast lineages. Then, the classification and structural characteristics of HLA molecules were elucidated. Finally, the presence of HLA-C and non-classical HLA-Ib molecules (HLA-E, HLA-F, and HLA-G) in various trophoblasts and cell lines, as well as their potential role in establishing and maintaining normal pregnancy were also discussed. Together, this review will help people comprehensively understand the complex immune interactions between maternal and fetal crosstalk during pregnancy and ultimately better understand the physiological and pathological etiologies of pregnancy.

Systemic Characterization of Novel Immune Cell Phenotypes in Recurrent Pregnancy Loss.

Recurrent pregnancy loss (RPL) is a disturbing disease in women, and 50% of RPL is reported to be associated with immune dysfunction. Most previous studies of RPL focused mainly on the relationship between RPL and either T cells or natural killer (NK) cells in peripheral blood and the decidua; few studies presented the systemic profiles of the peripheral immune cell subsets in RPL women. Herein, we simultaneously detected 63 immune cell phenotypes in the peripheral blood from nonpregnant women (NPW), women with a history of normal pregnancy (NP) and women with a history of RPL (RPL) by multi-parameter flow cytometry. The results demonstrated that the percentages of naïve CD4+ T cells, central memory CD4+ T cells, naïve CD8+ T cells, mature NK cells, Vδ1+ T cells and the ratio of Vδ1+ T cells/Vδ2+ T cells were significantly higher in the RPL group than those in the NPW and NP groups, whereas the percentages of terminal differentiated CD4+ T cells, effective memory CD4+ T cells, immature NK cells and Vδ2+ T cells were significantly lower in the RPL group than those in the NPW and NP groups. Interestingly, we found that peripheral T helper (TPH) cells were more abundant in the NPW group than in the NP and RPL groups. In addition, we also determined the 5th percentile lower limit and 95th percentile upper limit of the significantly changed immunological parameters based on the files of the NPW group. Taken together, this is the first study to simultaneously characterize the multiple immune cell subsets in the peripheral blood at a relatively large scale in RPL, which might provide a global readout of the immune status for clinicians to identify clinically-relevant immune disorders and guide them to make clear and individualized advice and treatment plans.