Molecular and Immunologic Aspects of the Nonclassical HLA Class I Antigen HLA-G: Evidence for an Important Role in the Maternal Tolerance of the Fetal Allograft (original) (raw)
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Proceedings of the National Academy of Sciences, 1997
HLA-G is a nonclassical major histocompatibility complex class I molecule selectively expressed on cytotrophoblasts at the feto–maternal interface, where it may play an important role in maternal tolerance of the fetus. We provide direct evidence under physiological conditions that supports the role of HLA-G in protecting cytotrophoblasts against natural killer (NK) cytolysis in 6 semiallogenic combinations of maternal uterine NK cells and their own trophoblast counterparts, as well as in 20 allogenic combinations of maternal uterine NK cells and trophoblasts from different mothers. We show that, in all cases studied, this HLA-G-mediated protection was abolished by treatment of cytotrophoblasts with an HLA-G-specific mAb. The HLA class I-negative K562 cell line transfected with the predominant HLA-G1 isoform results in similar protection and abolition from maternal uterine NK lysis. Because maternal uterine NK cells express killer inhibitory receptors for HLA-G, we conclude that the...
Biology of Reproduction, 2002
The description of healthy individuals homozygous for the human leukocyte antigen-G (HLA-G) null allele raised doubts about the role of HLA-G in fetal-maternal tolerance. In light of recent results, we discuss this point by considering the potential activity of this null allele that might, indeed, produce functional truncated HLA-G molecules. In this context, we have recently described that, like the full-length HLA-G1, the HLA-G2,-G3, and-G4 truncated isoforms may be expressed at the cell surface and may modulate both innate and acquired immune responses. embryo, immunology, placenta, pregnancy, trophoblast A key role in fetal-maternal immune tolerance has been attributed to human leukocyte antigen-G (HLA-G), a nonclassical HLA class I tissue-specific molecule that is highly expressed on extravillous cytotrophoblasts [1, 2]. A striking feature of HLA-G is the alternative splicing of its primary transcript (Fig. 1), giving rise to four membrane-bound (HLA-G1,-G2,-G3, and-G4) and three soluble (HLA-G5,-G6, and-G7) proteins (Fig. 2A). The full-length HLA-G1 mRNA encodes a protein that is associated with  2-microglobulin and has classical HLA class I structure. The mRNA species encoding HLA-G2,-G3, and-G4 proteins are truncated by deleting exon 3 (␣ 2 domain), exons 3 and 4 (␣ 2 and ␣ 3 domains), and exon 4 (␣ 3 domain), respectively. Soluble isoforms of HLA-G molecule are encoded by mRNAs containing introns that generate premature stop codons. Presence of intron 4 in both HLA-G5 (full-length) and HLA-G6 (minus exon 3) mRNAs results in the lack of transmembrane domains of the protein and, thus, permits synthesis of soluble forms of HLA-G1-like and HLA-G2like molecules, respectively [3-5]. We recently identified a new alternatively spliced transcript, namely HLA-G7, that possesses a stop codon in intron 2, which gives rise to a
HLA-G-From Fetal Tolerance to a Regulatory Molecule in Inflammatory Diseases
Current Immunology Reviews, 2010
The Human Leukocyte Antigen G (HLA-G) is a non-classical class I MHC which is characterized by low polymorphism at the DNA level, limited tissue distribution in non-pathological conditions and the expression of both membrane-bound and soluble isoforms by alternative splicing. This molecule has become the object of interest because of its possible role in pregnancy maintenance. HLA-G seems to be involved in the induction and maintenance of tolerance between the mother immune system and the semi-allogeneic fetus at the fetal-placentary interface, and also seems to play an important role in embryo implantation. Besides, several studies point out to a broader immunoregulatory role for this molecule. Here we review the potential roles of the HLA-G molecule on the immune system, the unique regulatory region of its gene, the influence of gene polymorphisms on HLA-G expression, as well as several situations in which this molecule has been involved, such as pregnancy, transplantation, cancer, viral infections and, more recently, inflammatory diseases.
HLA-G*0105N Null Allele Encodes Functional HLA-G Isoforms1
Biology of Reproduction, 2005
Expression of the nonclassical HLA class I antigen, HLA-G, is associated with immune tolerance in view of its role in maintaining the fetus in utero, allowing tumor escape, and favoring graft acceptance. Expressed on invasive trophoblast cells, HLA-G molecules bind inhibitory receptors on maternal T lymphocytes and NK cells, thereby blocking their cytolytic activities and protecting the fetus from maternal immune system attack. The HLA-G gene consists of 15 alleles, including a null allele, HLA-G*0105N. HLA-G*0105N presents a single base deletion, preventing translation of both membrane-bound (HLA-G1) and fulllength soluble isoforms (HLA-G5) as well as of the spliced HLA-G4 isoform. The identification of healthy subjects homozygous for this HLA-G null allele suggests that the HLA-G*0105N allele may generate other HLA-G isoforms, such as membrane-bound HLA-G2 and-G3 and the soluble HLA-G6 and-G7 proteins, which may substitute for HLA-G1 and-G5, thus assuming the immune tolerogeneic function of HLA-G. To investigate this point, we cloned genomic HLA-G*0105N DNA and transfected it into an HLA-class I-positive human cell line. The results obtained indicated that HLA-G proteins were indeed present in HLA-G*0105N-transfected cells and were able to protect against NK cell lysis. These findings emphasize the role of the other HLA-G isoforms as immune tolerogeneic molecules that may also contribute to maternal tolerance of the semiallogenic fetus as well as tumor escape and other types of allogeneic tissue acceptance.
The crucial immunological function of the classical human major histocompatibility complex (MHC) class I molecules, human histocompatibility leukocyte antigen (HLA)-A, -B, and -C, is the presentation of peptides to T cells. A secondary function is the inhibition of natural killer (NK) cells, mediated by binding of class I molecules to NK receptors. In contrast, the function of the nonclassical human MHC class I molecules, HLA-E, -F, and -G, is still a mystery. The specific expression of HLA-G in placental trophoblast suggests an important role for this molecule in the immunological interaction between mother and child. The fetus, semiallograft by its genotype, escapes maternal allorecognition by downregulation of HLA-A and HLA-B molecules at this interface. It has been suggested that the maternal NK recognition of this downregulation is balanced by the expression of HLA-G, thus preventing damage to the placenta. Here, we describe the partial inhibition of NK lysis of the MHC class I negative cell line LCL721.221 upon HLA-G transfection. We present three NK lines that are inhibited via the interaction of their NKAT3 receptor with HLA-G and with HLA-Bw4 molecules. Inhibition can be blocked by the anti-NKAT3 antibody 5.133. In conclusion, NK inhibition by HLA-G via NKAT3 may contribute to the survival of the fetal semiallograft in the mother during pregnancy. on
HLA-G in reproduction: studies on the maternal–fetal interface
Human Immunology, 2000
For more than a decade, investigators have known that membrane-bound and soluble isoforms of the HLA class Ib molecule, HLA-G, are present at the maternal-fetal interface. Although it is clear that extravillous cytotrophoblast cells are major producers, other cells may also contribute. Recent studies in our laboratory raised the question of whether soluble isoforms might reach the maternal and/or fetal blood circulation. A capture enzyme-linked immunoabsorbent assay (ELISA) identified soluble HLA-G (sHLA-G) in maternal blood throughout pregnancy but failed to detect sHLA-G in cord sera. Further studies suggested that the circulating proteins may be either free heavy chain (sHLA-G1 and/or sHLA-G2) or exclusively sHLA-G2. To study the potential function(s) of the soluble isoforms to modulate local or systemic immunity in mothers, we generated recombinant sHLA-G1 and -G2 in both prokaryotic and eukary-otic systems. Preliminary experiments conducted using DNA microarray analysis suggest that sHLA-G is capable of modulating gene expression in blood mononuclear leukocytes. Potential local targets were also identified; decidual and placental macrophages but not trophoblast cells contained mRNA encoding two of the known receptors for HLA-G, ILT2 and ILT4. Collectively, the studies are consistent with the hypothesis that sHLA-G produced at the maternal-fetal interface targets to the cells of the monocyte/macrophage lineage and modulates their functions for the benefit of pregnancy.
Role of HLA-G and other immune mechanisms in pregnancy
Central European Journal of Biology, 2013
Pregnancy loss (abortion) and pre-eclampsia represent the most common disorders in pregnant women. Besides infection, there are anatomical, endocrinological, genetic and immunological factors that can induce pregnancy disorders. Because the exact mechanisms of physiological pregnancy maintenance are still not clearly understood, the search for genes and proteins fulfilling this role is still in progress. One of the immune molecules that plays a beneficial role in pregnancy is the nonclassical HLA-G molecule. The molecule is mainly expressed on trophoblast cells in the foetal placenta and induces the immune tolerance of the foetus via its interaction with inhibitory receptors on maternal NK cells and CD8 + T lymphocytes. In relation to pregnancy disorders, associations between HLA-G polymorphism, HLA-G level and HLA-G function were described. Thus, the HLA-G molecule can be used as a new diagnostic marker and, potentially, for the future therapy of pregnancy disorders.
Proceedings of the National Academy of Sciences, 1999
Trophoblastic cells lack classical HLA class I and class II molecules but express HLA-G1. Although this may prevent allorecognition by maternal T cells, it renders trophoblastic cells potentially susceptible to lysis by natural killer (NK) cells. As shown here, only a fraction of peripheral-blood NK cells in pregnant women express the HLA-G1-specific CD94/NKG2A and/or LIR-1 receptors. However, all NK cells isolated from maternal decidua during the first trimester expressed either one or both of these receptors. Perhaps more importantly, a fraction of cells expressed p49, an HLA-G1-specific inhibitory receptor, undetectable in peripheral-blood NK cells. p49 was expressed on virtually all NK cells isolated from placenta at term. Functional analyses revealed that the HLA class I-negative 221 lymphoblastoid cell line transfected with HLA-G1 was only partially protected from lysis by peripheral-blood NK cells isolated from pregnant women, whereas it was fully protected from decidual NK cells. As indicated by the addition of specific antibodies to cytolytic tests, all the above receptors contributed to HLA-G1 recognition by decidual NK cells, although p49 would appear to play a predominant role.