Review
Co-Signaling Molecules in Maternal–Fetal Immunity

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Co-signaling molecules, such as those involved in regulatory immune checkpoints [including programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), as well as others], have important modulatory effects on tumors, as well as in transplantation, infections, and autoimmune diseases. Thus, they have recently been highlighted as potential diagnostic and therapeutic targets for various pathologies.

During normal pregnancy, the fetus is considered as a semiallogeneic transplant. Meanwhile, the immune defense against pathogens must remain uncompromised. Therefore, maternal–fetal tolerance is a special immunological phenomenon.

Recently, co-signaling molecules have been found to be spatiotemporally expressed in the gravid uterus and to be involved in pregnancy maintenance by regulating maternal–fetal immunity and assisting decidual vascular remodeling. It is hypothesized that dysregulation of these molecules could lead to pregnancy loss and pregnancy complications.

The incidence of pregnancy-related diseases is still high without efficacious strategies for diagnosis and treatment; thus, further evaluation and intervention of co-signaling molecules may be helpful in this respect.

Physiologically, a successful pregnancy requires the maternal immune system to recognize and tolerate the semiallogeneic fetus, and allow for normal invasion of trophoblasts. Thus, pregnancy complications are considered to be associated with dysfunctional maternal–fetal crosstalk. Co-signaling molecules are a group of cell surface molecules that positively or negatively modulate the immune response. Well studied in the fields of oncology and transplantation, they are also suggested to be involved in maternal–fetal crosstalk. Here, we review the latest knowledge on the expression and function of such co-signaling molecules, highlighting their immunoregulatory roles in maternal–fetal tolerance and decidual vascular remodeling, and their involvement in pathological pregnancies. This review may instruct future basic research on, and clinical applications for, maternal–fetal immunity.

Section snippets

Pregnancy, Immunology, and Co-Signaling Molecules

Pregnancy is a unique type of immunological process. To achieve successful pregnancy, the maternal immune system must accept the semiallogeneic (see Glossary) fetus that carries paternal antigens to allow for trophoblast invasion while preserving immune defense mechanisms against pathogens. However, the mechanisms controlling these unique immunological behaviors, and the harmonious crosstalk between maternal- and fetal-derived cells, remain poorly understood [1]. Given that dysregulation of

Co-Signaling Network

The concept of co-signals originated from the model of lymphocyte activation. According to the classic ‘two-signal model’ [7], lymphocytes remain unresponsive after exposure to the first signal, namely the recognition of antigens through T cell or B cell receptors (TCRs or BCRs). Lymphocytes are only fully activated after being stimulated by a second signal (co-signal) from the interaction between receptors on lymphocytes and their corresponding co-stimulating ligands on antigen-presenting cells

Co-Signaling Molecules in Human Pregnancy

Expression of Co-Signaling Molecules in Normal Pregnancy and RSA

At approximately 5 weeks after implantation, the human placenta is formed from both fetal-derived trophoblasts and the maternal-derived decidua. The placenta constitutes an interface connecting the mother and the fetus, which is known as the ‘maternal–fetal interface’ [23]. It is a highly dynamic tissue complementing the fetus, which develops rapidly through gestation, and it is the primary site of nutrient and gas exchange between

Co-Signaling Molecules in Murine Pregnancy

Murine models have also been used to gain further understanding of the role of co-signaling molecules in pregnancy. Indeed, in vivo blockade, deletion, or enhancement of co-signaling molecules, which could not be achieved in humans, could change the phenotype and function of maternal immune cells and lead to different pregnancy outcomes in such murine models. These, in turn, might link specific cellular processes to pathophysiological events and provide evidence that co-signaling-related immune

Concluding Remarks

The survival of a semiallogeneic fetus requires balanced maternal–fetal crosstalk, where immune regulation has an important role. Recent studies have shed new light on the involvement of co-signaling molecules in maternal–fetal immunity. These molecules are widely present at the maternal–fetal interface and are key immunomodulators providing the fetus with a suitable immunological microenvironment throughout pregnancy. They regulate the immunological and biological behaviors of embryonic

Acknowledgments

This study was supported by the National Basic Research Program of China (2015CB943300); National Nature Science Foundation of China (81630036, 91542116, 31570920, 81490744); the Key Project of Shanghai Municipal Education Commission (14ZZ013), and the Key Project of Shanghai Basic Research from Shanghai Municipal Science and Technology Commission (12JC1401600).

Glossary

Allogeneic
genetically dissimilar and, hence, immunologically incompatible between individuals of the same species.
Antigen-presenting cells (APCs)
display antigen complexes to T cells via TCRs. Professional APCs, including macrophages, B cells and dendritic cells, present foreign antigens to T helper cells, while other cell types can present antigens originating inside the cell to cytotoxic T cells.
Basal plate
during pregnancy, changes in the placenta involve the disappearance of the greater

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