Research progress of maternal-fetal tolerance

Abstract

Development of the allogeneic fetus in the maternal uterus represents an immunological paradox. Successful pregnancy requires the maternal immune system to tolerate the semi-allogeneic fetus. A failure in immune tolerance may result in abnormal pregnancies, such as recurrent spontaneous abortion. These call for a better understanding of the mechanisms leading to maternal-fetal tolerance. As the only exception to the traditional immunological principles, maternal-fetal tolerance has always been the focus of attention in the fields of reproductive immunology. Embryos express paternal antigens that are foreign to the mother, but the mother provides a special immune milieu at the fetal-maternal interface to permit rather than reject the embryo growth in the uterus until parturition by establishing precise crosstalk between the mother and the fetus. The formation of a functional synapse of the invading fetal trophoblsats, maternal immune cells and decidual stromal cells have now been identified. An improved mechanistic understanding of maternal-fetal tolerance is emerging during the last century. During early pregnancy, the developing decidua undergoes dramatic changes in response to invading trophoblasts. Extravillous trophoblast (EVT) cells do not express major histocompatibility complex (MHC) class I human leukocyte antigens (HLA)-A and HLA-B, which are the main causes of CD8+ T cell-mediated rejection. However, HLA-C and HLA-G, highly expressed on EVT cells, can elicit a direct tolerant response by NK cells in most cases. Furthermore, maternal immune cells could be educated by embryonic trophoblasts to develop a unique phenotype and tolerate the fetus. Decidual stromal cells (DSCs) are the predominant cell type of the maternal decidua and play a key role in embryo implantation and placentation. Apart from nutritive and endocrine functions, DSCs are believed to be involved in many immune activities, such as cytokine production and antigen presentation, and regulate the decidual immune responses that may lead to either a successful pregnancy or miscarriage. Howerer, there are still unanswered questions in the maintenance of pregnancy, including the poorly understood phenomenon of maternal tolerance to the allogeneic conceptus, and the remarkable biological roles of placental trophoblasts that invade the uterine wall and decidual stromal cells which are the largest number of cells in the decidua. Here we review the previous research results in the field, with a special focus on the establishment and maintenance mechanism of maternal-fetal tolerance based on the maternal-fetal crosstalk. Nevertheless, recent advances in molecular biology have dramatically enhanced our knowledge of the immunobiology of the maternal-fetal interface. Insights into maternal-fetal tolerance will not only advance our understanding of normal pregnancy but also may be helpful on how immune tolerance can be applied in therapeutic strategies to prevent pregnancy loss. Further research in these areas will give us more avenues for preventing pregnancy complication related to faulty maternal-fetal immune interactions.