The Relevance of Peripheral Immune Tolerance in Normal Pregnancy and its Potential Failure in Gestation-Associated Diseases

Transforming growth factor-β (TGF-β) is composed of three isoforms, TGF-β1, TGF-β2, and TGF-β3. TGF-β1 is a cytokine with multiple biological functions that has been studied extensively. It plays an important role in regulating the differentiation of immune cells and maintaining immune cell functions and immune homeostasis. Pregnancy is a carefully regulated process. Controlled invasion of trophoblasts, precise coordination of immune cells and cytokines, and crosstalk between trophoblasts and immune cells play vital roles in the establishment and maintenance of normal pregnancy. In this systematic review, we summarize the role of TGF-β1 in regulating fetal-maternal immune tolerance in healthy and pathological pregnancies. During healthy pregnancy, TGF-β1 induces the production of regulatory T cells (Tregs), maintains the immunosuppressive function of Tregs, mediates the balance of M1/M2 macrophages, and regulates the function of NK cells, thus participating in maintaining fetal-maternal immune tolerance. In addition, some studies have shown that TGF-β1 is dysregulated in patients with recurrent spontaneous abortion or preeclampsia. TGF-β1 may play a role in the occurrence and development of these diseases and may be a potential target for the treatment of these diseases.

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Decidual NR2F2-Expressing CD4+ T Cells Promote TH2 Transcriptional Program During Early Pregnancy

Frontiers in Immunology ◽

10.3389/fimmu.2021.670777 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yikong Lin ◽

Di Zhang ◽

Yangyang Li ◽

Yunyun Li ◽

Bin Li ◽

...

Keyword(s):

T Cells ◽

Cell Fate ◽

Immune Tolerance ◽

Early Pregnancy ◽

Normal Pregnancy ◽

Cell Fate Specification ◽

Prediction And Prevention ◽

Potential Biomarker ◽

Unexplained Recurrent Spontaneous Abortion ◽

Th2 Differentiation

A unique immunotolerant microenvironment with Th2 bias in the decidua provides an essential security for successful pregnancy. The disorganized maternal-fetal immune tolerance contributes to more than 50% of unexplained recurrent spontaneous abortion (RSA). How the Th2 bias is developed at the maternal-fetal interface remains undefined. NR2F2, a member of steroid/thyroid nuclear receptor superfamily, is endowed with diverse importance in cell-fate specification, organogenesis, angiogenesis, and metabolism. Here, we showed that NR2F2 was absolutely highly expressed in decidual CD4+T(dCD4+T) cells, but not in peripheral circulating CD4+T cells during early pregnancy. Decidual NR2F2-expressing CD4+T cells dominantly produced Th2 cytokines. In unexplained RSA patients, NR2F2 expression in dCD4+T cells was significantly decreased, accompanied with disordered phenotype of dCD4+T cells. Furthermore, overexpression of NR2F2 promoted the Th2 differentiation of naive CD4+T cells. Immunoprecipitation experiment confirmed the binding relationship between GATA-3 and NR2F2, which implied GATA-3 may be an important interactive element involved in the immunoregulatory process of NR2F2. This study is the first to reveal a previously unappreciated role for NR2F2-mediated dCD4+T cells in maternal-fetal immune tolerance and maintenance of normal pregnancy, in the hope of providing a potential biomarker for prediction and prevention of clinical unexplained RSA.

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Characterization of dendritic cell (DC)-10 in recurrent miscarriage and recurrent implantation failure

Reproduction ◽

10.1530/rep-19-0172 ◽

2019 ◽

Vol 158 (3) ◽

pp. 247-255

Author(s):

Su Liu ◽

Hongxia Wei ◽

Yuye Li ◽

Lianghui Diao ◽

Ruochun Lian ◽

...

Keyword(s):

Mhc Class Ii ◽

Immune Tolerance ◽

Recurrent Miscarriage ◽

Critical Role ◽

Costimulatory Molecule ◽

Normal Pregnancy ◽

Implantation Failure ◽

Recurrent Implantation Failure ◽

Human Pregnancy

During pregnancy, the maternal immune system must tolerate the persistence of semi-allogeneic fetus in the maternal tissue. Inadequate recognition of fetal antigens may lead to pregnancy complications, such as recurrent miscarriage (RM) and recurrent implantation failure (RIF). Dendritic cells (DCs) are key regulators of protective immune responses and the development and maintenance of tolerance. Regarding that DCs are important in the establishment of immune tolerance in human pregnancy, it would be important to study the microenvironment in which DCs reside or are activated may affect their functions toward tolerance rather than active immune response. IL-10 plays a critical role in the maintenance of normal pregnancy, and the increased production of IL-10 is associated with successful pregnancy. In this study, we provide an in-depth comparison of the phenotype and cytokine production by DC-10 and other DC subsets, such as iDC and mDC. CD14+ monocyte-derived DCs were differentiated in the presence of IL-10 (DC-10) in vitro from ten normal fertile controls, six RM women and seven RIF women, and characterized for relevant markers. DC-10 was characterized by relatively low expression of costimulatory molecule CD86, as well as MHC class II molecule HLA-DR, high expression of tolerance molecules HLA-G, ILT2, ILT4 and immunosuppressive cytokine IL-10, but produced little or no proinflammatory cytokines, such as TNF-α, IL-6 and IL-12p70. Our study provides a better understanding of the phenotypical properties of DC-10, which may participate in the complex orchestration that leads to maternal immune tolerance and homeostatic environment in human pregnancy.

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Crosstalk Between Trophoblasts and Decidual Immune Cells: The Cornerstone of Maternal-Fetal Immunotolerance

Frontiers in Immunology ◽

10.3389/fimmu.2021.642392 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ling Xu ◽

Yanhong Li ◽

Yifei Sang ◽

Da-Jin Li ◽

Meirong Du

Keyword(s):

Immune Tolerance ◽

Immune Cells ◽

Direct Interaction ◽

Basic Research ◽

Normal Pregnancy ◽

Therapeutic Strategies ◽

Maternal Immune System ◽

Reproductive Immunity ◽

Clinical Transformation ◽

Fine Adjustment

The success of pregnancy relies on the fine adjustment of the maternal immune system to tolerate the allogeneic fetus. Trophoblasts carrying paternal antigens are the only fetal-derived cells that come into direct contact with the maternal immune cells at the maternal–fetal interface. The crosstalk between trophoblasts and decidual immune cells (DICs) via cell–cell direct interaction and soluble factors such as chemokines and cytokines is a core event contributing to the unique immunotolerant microenvironment. Abnormal trophoblasts–DICs crosstalk can lead to dysregulated immune situations, which is well known to be a potential cause of a series of pregnancy complications including recurrent spontaneous abortion (RSA), which is the most common one. Immunotherapy has been applied to RSA. However, its development has been far less rapid or mature than that of cancer immunotherapy. Elucidating the mechanism of maternal–fetal immune tolerance, the theoretical basis for RSA immunotherapy, not only helps to understand the establishment and maintenance of normal pregnancy but also provides new therapeutic strategies and promotes the progress of immunotherapy against pregnancy-related diseases caused by disrupted immunotolerance. In this review, we focus on recent progress in the maternal–fetal immune tolerance mediated by trophoblasts–DICs crosstalk and clinical application of immunotherapy in RSA. Advancement in this area will further accelerate the basic research and clinical transformation of reproductive immunity and tumor immunity.

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