Endothelial cells in chorionic fetal vessels of first trimester placenta express HLA‐G

Blaschitz, Astrid; Lenfant, Françoise; Mallet, Valérie; Hartmann, Michaele; Bensussan, Armand; Geraghty, Daniel E.; Bouteiller, Philippe Le; Dohr, Gottfried

doi:10.1002/eji.1830271237

Cited by 150 publications

(82 citation statements)

References 33 publications

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“…Using this Ab, soluble HLA-G has been localized within the extravillous trophoblasts and has been reported in association with human villous cytotrophoblasts as well as in some cases with the syncytiotrophoblasts (5,14) and villous endothelial cells (34). Finally, some macrophages within the placental villi were also seen to express soluble HLA-G (14).…”

Section: Discussionmentioning

confidence: 91%

“…The resulting protein has a novel carboxyl terminus and is able to complex with ␤ 2 -microglobulin, but would be released from the cell due to the lack of a transmembrane domain (12,13). In addition to the placenta (14,34), soluble HLA-G has also been reported in CD4 ϩ T cells (20), activated monocytes (35), thymic epithelium (36), and lung tumor cells (37). It is intriguing that like HLA-G, the Mamu-AG gene also is alternatively spliced to give rise to a soluble molecule.…”

Section: Discussionmentioning

confidence: 99%

“…In one tubule we noted high expression of membrane-bound Mamu-AG on a cellular aggregate (not shown) that also stained positively for the macrophage marker CD68. The expression of HLA-G has been noted in macrophages invading psoriatic skin lesions (45) and in activated macrophages and dendritic cells in lung tumors (34,46). Although the expression of soluble or membrane-bound HLA-G in placental macrophages is not fully resolved (5,14,41), the rhesus monkey may be an experimental model in which to explore the functional significance of soluble nonclassical MHC class I molecules in vivo.…”

Section: Discussionmentioning

confidence: 99%

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A Soluble Isoform of the Rhesus Monkey Nonclassical MHC Class I Molecule Mamu-AG Is Expressed in the Placenta and the Testis

Ryan¹,

Grendell²,

Geraghty

et al. 2002

The Journal of Immunology

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The nonclassical MHC class I locus HLA-G is expressed primarily in the placenta, although other sites of expression have been noted in normal and pathological situations. In addition, soluble HLA-G isoforms have been detected in the serum of pregnant and nonpregnant women as well as men. The rhesus monkey placenta expresses a novel nonclassical MHC class I molecule Mamu-AG, which has features remarkably similar to those of HLA-G. We determined that the rhesus placenta expresses Mamu-AG mRNA (Mamu-AG5), retaining intron 4 as previously noted in HLA-G5. Immunostaining experiments with Ab 16G1 against the soluble HLA-G5 intron 4 peptide demonstrated that an immunoreactive protein(s) was present in the syncytiotrophoblasts of the chorionic villi of the rhesus placenta, within villous cytotrophoblasts, and occasionally within cells of the villous stroma. The Mamu-AG5 mRNA was readily detected in rhesus testis (although not in ejaculated sperm). Whereas an Ab against membrane-bound Mamu-AG stained few cells, primarily in the interstitium of the testis, there was consistent immunostaining for Mamu-AG5 in cells within the seminiferous tubules, which was corroborated by localization of Mamu-AG mRNA by in situ hybridization. While primary spermatocytes were negative, Sertoli cells, spermatocytes, and spermatids were consistently positive for 16G1 immunostaining. The specific recognition of the soluble Mamu-AG isoform was confirmed by Western blotting of Mamu-AG5 expressed in heterologous cells. The results demonstrate that a soluble nonclassical MHC class I molecule is expressed in the rhesus monkey placenta and testis, and confirm and extend the unique homology between HLA-G and the rhesus nonclassical molecule Mamu-AG.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A Soluble Isoform of the Rhesus Monkey Nonclassical MHC Class I Molecule Mamu-AG Is Expressed in the Placenta and the Testis

Ryan¹,

Grendell²,

Geraghty

et al. 2002

The Journal of Immunology

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“…HLA-G molecules are involved in the inhibition of both T and natural killer (NK) cell-mediated cytolysis through interaction with the ILT2, ILT4, and KIR2DL4 receptors (8)(9)(10)(11)(12). The constitutive expression of HLA-G proteins in extravillous cytotrophoblasts (13), and in a few other tissues (14)(15)(16), correlates with high transcriptional activity, whereas levels of HLA-G gene transcripts are generally low or absent in other tissues (17). HLA-G is also activated in virusinfected cells (18,19), in tumoral (20)(21)(22)(23)(24)(25)(26)(27)(28)(29) and inflammatory (30)(31)(32) pathologies, and during allogenic processes (33)(34)(35).…”

mentioning

confidence: 99%

HLA-G gene repression is reversed by demethylation

Moreau

Mouillot

Rousseau

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

141

134

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The HLA-G molecule plays an important role in immune tolerance, protecting the fetus from maternal immune attack, and probably contributes to graft tolerance and tumor escape from the host immune system. HLA-G expression is tightly regulated and involves mechanisms acting in part at the transcriptional level. Nevertheless, almost all regulatory sequences that govern constitutive and inducible HLA class I gene transcription are disrupted in the HLA-G gene promoter, suggesting an unusual regulatory process. In further investigating the molecular mechanisms of HLA-G gene activation, we evaluated the influence of epigenetic mechanisms on seven HLA-G-negative cell lines that exhibit various phenotypes. Exposure of cells to histone deacetylase inhibitors, or to the demethylating agent 5-aza-2 -deoxycytidine, revealed that HLA-G gene transcription is inhibited by DNA methylation. Reversal of methylation-mediated repression may directly induce HLA-G cellsurface expression, supporting the idea that HLA-G might be activated by such a mechanism during malignancy, inflammation, and allogenic reactions.

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“…U-373MG(U373) human astrocytoma cells (ATCC), U373/G [U373 cells stably transfected with pcDNA-G1 (Blaschitz et al, 1997)] and U373/G-IE1-pp65 [U373/G cells stably transfected with IE1-pp65 cDNA (Vaz-Santiago et al, 2001)] were used as HCMV-infected target cells.…”

Section: Methodsmentioning

confidence: 99%

Induction of HLA-G-restricted human cytomegalovirus pp65 (UL83)-specific cytotoxic T lymphocytes in HLA-G transgenic mice

Lenfant

Pizzato

Liang

et al. 2003

Journal of General Virology

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The non-classical major histocompatibility complex class I molecule HLA-G is expressed mainly by extravillous trophoblasts at the materno-foetal interface. HLA-G has been found to bind endogenously processed nonameric peptides but its function as a restriction element for a cytotoxic T cell response to viruses with tropism for trophoblastic cells has never been demonstrated. In this study, candidate viral peptides derived from human cytomegalovirus (HCMV) pp65 (UL83), which stabilized the HLA-G molecule on HLA-G-transfected T2 cells, were identified. The specific antipp65 cytotoxic T lymphocyte (CTL) response restricted by HLA-G in triple transgenic mice (HLA-G, human b2m, human CD8a) was then investigated by injection of dendritic cells loaded with synthetic pp65-derived peptides or by infection with canarypox virus expressing pp65. Results showed that CTLs from HLA-G mice have the capacity to kill target cells either infected with recombinant vaccinia viruses expressing pp65 or loaded with specific pp65-derived peptides using HLA-G as an antigen-presenting molecule. It was also demonstrated that these HLA-G-restricted pp65-specific T cells are able to kill the human astrocytoma cell line U373, which was transfected with HLA-G and infected with HCMV. Moreover, using HLA-G tetramers refolded with a synthetic pp65-derived peptide, peptide-specific CD8 + cells restricted by HLA-G have been detected in vivo. These findings provide the first evidence that HLA-G can select anti-HCMV-restricted CTLs in vivo, although the potency of this cytolytic response is limited (20-25 %). The weak HLA-Grestricted anti-HCMV response is probably due to HLA-G-mediated inhibitory signals on the development of an antiviral CTL response. INTRODUCTIONDuring pregnancy, the placenta is the first barrier that protects the foetus from pathogens. It is of relevance, therefore, that trophoblast cells in placental tissues lack major histocompatibility (MHC) class I expression. These highly polymorphic MHC molecules, HLA-A and HLA-B, play a central role in the detection and elimination of infected cells by CD8 + T cells and natural killer (NK) cells. However, despite the general lack of classical MHC molecules, extravillous trophoblasts, a subpopulation of trophoblasts that is in direct contact with maternal cells, express low levels of HLA-C and at a higher extent, the non-classical HLA-Ib molecules HLA-G and HLA-E (Kovats et al., 1990;Le Bouteiller et al., 1999;King et al., 2000), which are accompanied by abundant expression of transporter-associated proteins (TAP) (Clover et al., 1995). The non-classical HLA-Ib molecule HLA-E binds preferentially to leader peptides of many MHC class I molecules (Braud et al., 1998;Lee et al., 1998) and these complexes function as ligands for CD94/NKG2 receptors on NK cells . HLA-G molecules have a peptide-binding groove that is homologous to those of classical MHC class I molecules. In addition, HLA-G was shown to present nonameric peptides derived from a variety of intracellular proteins (Diehl et al., 199...

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Endothelial cells in chorionic fetal vessels of first trimester placenta express HLA‐G

Cited by 150 publications

References 33 publications

A Soluble Isoform of the Rhesus Monkey Nonclassical MHC Class I Molecule Mamu-AG Is Expressed in the Placenta and the Testis

A Soluble Isoform of the Rhesus Monkey Nonclassical MHC Class I Molecule Mamu-AG Is Expressed in the Placenta and the Testis

HLA-G gene repression is reversed by demethylation

Induction of HLA-G-restricted human cytomegalovirus pp65 (UL83)-specific cytotoxic T lymphocytes in HLA-G transgenic mice

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