HLA-G functions as a restriction element and a transplantation antigen in mice

Horuzsko, Anatolij; Antoniou, Jane; Tomlinson, Peter; Portik-Dobos, Vera; Mellor, Andrew L.

doi:10.1093/intimm/9.5.645

Cited by 46 publications

(23 citation statements)

References 6 publications

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“…Induction of proliferation in C57BL/6 mouse T cells by crosslinking of Qa-2 had previously been demonstrated [23,[35][36][37][38]. Because only 1% of healthy human T cells express HLA-G protein [44], to perform HLA-G crosslinking experiments on T cells, we used HLA-G transgenic mice on a Qa-2 negative background [45].…”

Section: Discussionmentioning

confidence: 99%

HLA-G Is Found in Lipid Rafts and Can Act as a Signaling Molecule

2007

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HLA-G protein is the functional homolog of Qa-2, the product of the mouse preimplantation embryo development (Ped) gene. Embryos expressing Qa-2 on the cell surface exhibit a faster rate of preimplantation cleavage and preferential survival in utero compared with Qa-2-negative embryos. Qa-2 is glycosylphosphatidylinositol (GPI) linked in the cell membrane. As a result, Qa-2 proteins cluster in cholesterol- and sphingolipid-rich lipid raft microdomains in the cell membrane and can signal via raft-associated intracellular signaling molecules. Using T cells as a model system, cross-linking of Qa-2 on the cell membrane has been shown to induce proliferation of resting cells. HLA-G, like Qa-2, lacks a cytoplasmic domain capable of transducing signals from the cell surface to the nucleus, but unlike Qa-2, HLA-G has a short six-amino acid cytoplasmic tail rather than a GPI anchor. To test whether HLA-G, like Qa-2, is located in lipid rafts and can act as a signaling molecule, we used an HLA-G transgenic mouse system. T cells were isolated and tested for HLA-G expression by immunofluorescence and for localization of HLA-G in lipid rafts by immunofluorescence and Western blotting. Next, the T cells were cross-linked with anti-HLA-G antibody to test for induction of proliferation. Our novel results show that HLA-G, like GPI-linked Qa-2, is present in lipid rafts in the cell membrane and can act as a signaling molecule to induce proliferation of resting T cells.

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Section: Discussionmentioning

confidence: 99%

HLA-G Is Found in Lipid Rafts and Can Act as a Signaling Molecule

2007

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“…HLA‐G is a nonclassical MHC‐I molecule that can be expressed as seven isoforms owing to alternative splicing of the primary transcript . Among them, the most studied are membrane‐bound HLA‐G1 and soluble HLA‐G5, both associated to β2m, necessary for their stable conformation . In healthy individuals, HLA‐G tissue distribution is restricted but can be induced under pathological conditions such as organ transplantation, malignant transformation, viral infection, inflammatory and autoimmune diseases .…”

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confidence: 99%

In vivo evidence that secretion of HLA‐G by immunogenic tumor cells allows their evasion from immunosurveillance

Loumagne

Baudhuin

Favier

et al. 2014

Intl Journal of Cancer

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Human leukocyte antigen‐G (HLA‐G) expression by tumors has been evidenced in numerous malignancies in association with poor prognosis and resistance to immunotherapy in humans. Particularly, soluble form of HLA‐G was measured at high concentrations in malignant effusions and plasma from cancer patients, and inhibits antitumor immune cells in vitro through interaction with immunoglobulin‐like transcript (ILT) receptors. Nevertheless, in vivo study demonstrating that HLA‐G secretion by tumor cells allows their escape from immunosurveillance remained to be established. Despite nondescribed murine homolog, direct functional interaction of HLA‐G with murine paired immunoglobulin‐like receptor (PIR)‐B, ortholog of human ILT receptors, enables to investigate its role in vivo. Immunocompetent mice were injected either with syngeneic tumor cells co‐expressing HLA‐G5, the main soluble HLA‐G isoform, and the conformation stabilizer human β2‐microglubulin (hβ2m), or with hβ2m+HLA‐G5− tumor cells. hβ2m expressed at both tumor cell surface acted as a tumor antigen triggering a specific humoral response. Interestingly, although hβ2m+HLA‐G5− tumors were rejected, secreted HLA‐G5 provided hβ2m+HLA‐G5+ tumors a protection against hβ2m‐elicited immune rejection, enabling such immunogenic tumors to grow similarly to a poorly immunogenic tumor. HLA‐G5 tumor expression was associated with local and peripheral immunosuppression, characterized by dampened anti‐hβ2m B‐cell response, quantitative and functional T‐and B‐cell defects, accumulation of myeloid‐derived suppressor cells able to inhibit T‐cell proliferation and reduced T‐ and B‐cell tumor infiltrate. Our study provides the first in vivo proof that soluble HLA‐G counteracts tumor rejection and reinforces the importance to consider HLA‐G as a promising target to optimize current cancer immunotherapies.

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“…Generation of peptide-specific CTLs. HLA-G transgenic mice (CBA/Ca, H-2 k , H-2K b /HLA-G; hb2m, hCD8a) (Horuzsko et al, 1997) at 6-8 weeks of age were used for experiments. Mice were bred and maintained in a specific-pathogen-free facility at the Medical College of Georgia, GA, USA.…”

Section: Methodsmentioning

confidence: 99%

“…It was proposed that HLA-G on trophoblast cells interacts with several inhibitory or triggering NK cell receptors to protect placental cells against the cytotoxic activity of NK cells (Lanier, 1999). Two reports using HLA-G transgenic mice have demonstrated that HLA-G molecules are recognized as a self-molecule capable of eliciting a cytotoxic T lymphocyte (CTL) response (Horuzsko et al, 1997;Schmidt et al, 1997). In humans, HLA-G expression has been detected also on thymic medullary epithelial cells (Crisa et al, 1997;Mallet et al, 1999) and HLA-G molecules were found to bind CD8a/a with an affinity similar to that observed with classical HLA molecules (Sanders et al, 1991), Human cytomegalovirus (HCMV) infection remains the most common congenital virus infection and is the cause of neurological defects that affect from 0?4 to 2?3 % of liveborn infants (Plotkin, 1994).…”

mentioning

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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HLA-G functions as a restriction element and a transplantation antigen in mice

Cited by 46 publications

References 6 publications

HLA-G Is Found in Lipid Rafts and Can Act as a Signaling Molecule

HLA-G Is Found in Lipid Rafts and Can Act as a Signaling Molecule

In vivo evidence that secretion of HLA‐G by immunogenic tumor cells allows their evasion from immunosurveillance

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

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