Abstract
Maternal-fetal immune-tolerance occurs throughout the whole gestational trimester, thus a mother can accept a genetically distinct fetus without immunological aggressive behavior. HLA-G, one of the non-classical HLA class I molecules, is restricted-expression at extravillous trophoblast. It can concordantly interact with various kinds of receptors mounted on maternally immune cells residing in the uterus (e.g. CD4+ T cells, CD8+ T cells, natural killer cells, macrophages, and dendritic cells) for maintaining immune homeostasis of the maternal-fetus interface. HLA-G is widely regarded as the pivotal protective factor for successful pregnancies. In the past 20 years, researches associated with HLA-G have been continually published. Indeed, HLA-G plays a mysterious role in the mechanism of maternal-fetal immune-tolerance. It can also be ectopically expressed on tumor cells, infected sites and other pathologic microenvironments to confer a significant local tolerance. Understanding the characteristics of HLA-G in immunologic tolerance is not only beneficial for pathological pregnancy, but also helpful to the therapy of other immune-related diseases, such as organ transplant rejection, tumor migration, and autoimmune disease. In this review, we describe the biological properties of HLA-G, then summarize our understanding of the mechanisms of fetomaternal immunologic tolerance and the difference from transplant tolerance. Furthermore, we will discuss how HLA-G contributes to the tolerogenic microenvironment during pregnancy. Finally, we hope to find some new aspects of HLA-G in fundamental research or clinical application for the future.
Highlights
Three decades ago, a unique human leukocyte antigen (HLA) like molecule, named HLA-G, was found to be highly expressed in extravillous trophoblast (EVT)
HLA-G expressed by invading EVT serves as a potential ligand for directly binding to cell surface receptors of leukocytes, including NK cells, T cells, B cells, and antigenpresenting cells (APC) residing in the maternal decidua
HLA-G was restrictedly expressed in EVT, which is the functional unit of the placenta, under the physiological status and well-accepted the key mediator of fetomaternal immunologic tolerance
Summary
A unique human leukocyte antigen (HLA) like molecule, named HLA-G, was found to be highly expressed in extravillous trophoblast (EVT). HLA-G, Maternal-Fetal Immune-Tolerance similar exon/intron structure and an 86% overall homology at the protein level with the classical class I genes HLA-A, -B, and – C, but a 5’ flanking region with distinctive 5’ regulatory elements. Despite complex regulation of the HLA-G gene, transcription only yields seven alternative mRNAs that encode seven different protein isoforms, namely; membrane-bound (HLA-G1, -G2, -G3, -G4) and soluble (HLA- G5, -G6, -G7) molecules (see Figure 1). The HLA-G1, -G2, and –G6 isoforms are preferentially expressed only in invading cytotrophoblasts, such as the terminal edge of trophoblast columns and the chorion membrane cytotrophoblasts cells, FIGURE 1 | The structure of HLA-G gene and its encoding isoforms generated by alternative splicing mRNAs. Novel HLA-G isoforms reported by Tronik-Le Roux D et al [20] (pin). These micro-environmental factors were present in maternal-fetal interplay to affect the HLA-G expression and sequentially its biological function
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