Affinage

HLA-G

HLA class I histocompatibility antigen, alpha chain G · UniProt P17693

Round 2 corrected
Length
338 aa
Mass
38.2 kDa
Annotated
2026-04-28
130 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HLA-G is a nonclassical MHC class I molecule with restricted expression on extravillous trophoblasts that functions as a master mediator of immune tolerance at the maternal–fetal interface and in other immunoprivileged contexts. Its truncated cytoplasmic tail impairs endocytosis, prolonging surface residence (PMID:9368631), and its primary transcript undergoes alternative splicing to produce at least four membrane-bound and three soluble isoforms, all capable of inhibiting NK- and CTL-mediated cytolysis (PMID:1570318, PMID:11290782). HLA-G presents peptides via a defined XI/LPXXXXXL motif (PMID:8805247) and forms disulfide-linked dimers through Cys-42 (PMID:12454284); it engages the inhibitory receptors ILT2 and ILT4 with 3–4-fold higher affinity than classical MHC-I to induce tolerogenic dendritic cells and regulatory T cells, KIR2DL4 from endosomes to elicit proangiogenic signaling, and CD8 on activated T cells to trigger Fas/FasL-mediated apoptosis (PMID:12853576, PMID:15770701, PMID:10190900, PMID:10843658). Trophoblast-specific expression is governed by a distal enhancer (Enhancer L, ~12 kb upstream) occupied by CEBP/GATA factors and looping to the promoter, with additional regulation by IL-10-dependent transcription, DNMT-1-mediated promoter methylation, a LINE1-based silencing element, and a 3′ UTR 14-bp insertion polymorphism that modulates mRNA stability (PMID:27078102, PMID:10330285, PMID:26116450, PMID:23002136, PMID:14602228).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1987 High

    Identification of HLA-G as a non-classical class I gene with a truncated cytoplasmic tail established it as structurally distinct from HLA-A/B/C and predicted unusual trafficking or signaling properties.

    Evidence Genomic cloning and sequencing revealing an in-frame stop codon shortening the cytoplasmic domain

    PMID:3480534

    Open questions at the time
    • No protein expression data yet
    • No functional consequence of tail truncation demonstrated
    • Tissue distribution unknown
  2. 1990 High

    Demonstrating that HLA-G protein is selectively expressed on first-trimester cytotrophoblasts but absent from lymphoid cells answered whether HLA-G had tissue-restricted expression and immediately implicated it in maternal–fetal immune regulation.

    Evidence 2D gel electrophoresis and immunoprecipitation on trophoblast and lymphoid cells; independent cDNA cloning from extravillous trophoblast and BeWo choriocarcinoma

    PMID:2295808 PMID:2326636

    Open questions at the time
    • Mechanism of tissue restriction unknown
    • Functional role at the maternal–fetal interface not yet demonstrated
  3. 1992 High

    Discovery of at least three alternatively spliced isoforms (including truncated forms lacking alpha2 or alpha2+alpha3 domains) expanded the functional repertoire of HLA-G beyond a single membrane-bound protein.

    Evidence RT-PCR with immunoprecipitation of [35S]-labeled proteins confirming three distinct protein products

    PMID:1570318

    Open questions at the time
    • Whether truncated isoforms reach the cell surface and are functional was unresolved
    • Soluble isoforms not yet characterized
  4. 1996 High

    Defining the HLA-G peptide-binding motif (XI/LPXXXXXL) established that HLA-G presents peptides analogously to classical MHC-I, raising the question of whether its immunomodulatory function requires specific peptide loading.

    Evidence Peptide elution from HLA-G-expressing LCL721.221 transfectants, pool sequencing, and peptide-binding assays

    PMID:8805247

    Open questions at the time
    • Identity of physiologically presented peptides at the maternal–fetal interface unknown
    • Whether peptide identity affects receptor engagement undetermined
  5. 1997 High

    Functional evidence that HLA-G1 and HLA-G2 isoforms both inhibit NK cell lysis, combined with demonstration that the truncated cytoplasmic tail impairs endocytosis, established HLA-G as a stable surface-resident NK inhibitory ligand functioning through the alpha1 domain.

    Evidence NK cytolysis assays with HLA-G1/G2-transfected K562 cells across 20 donors; surface biotinylation and chimeric construct endocytosis assays

    PMID:9144223 PMID:9368631

    Open questions at the time
    • Specific inhibitory receptors mediating NK inhibition not yet identified
    • Whether all truncated isoforms are functional was unknown
  6. 1999 High

    Identification of ILT2, ILT4, and KIR2DL4 as three distinct HLA-G receptors, together with the indirect pathway via HLA-E/CD94-NKG2A, resolved how HLA-G inhibits diverse immune effector cell types through both direct and indirect recognition systems.

    Evidence ILT4 ITIM signaling assays; recombinant KIR2DL4 binding to HLA-G+ cells with functional transfer into NK-92; HLA-E leader-sequence mutagenesis combined with ILT2-Ig and CD94/NKG2A blocking

    PMID:10190900 PMID:9531263 PMID:9933109

    Open questions at the time
    • Quantitative binding affinities for each receptor not yet measured
    • Signaling pathways downstream of each receptor not characterized
    • KIR2DL4 binding site on HLA-G unmapped
  7. 2000 High

    Showing that soluble HLA-G1 induces apoptosis in activated CD8+ T cells via CD8-dependent upregulation of CD95L/Fas revealed a cytotoxic effector deletion mechanism distinct from receptor-mediated inhibition.

    Evidence Affinity-purified sHLA-G1 with CD95-Fc, ZB4, and CD8 mAb blocking experiments

    PMID:10843658

    Open questions at the time
    • Whether this pathway operates in vivo at the maternal–fetal interface not shown
    • Threshold of sHLA-G1 concentration required for apoptosis undefined
  8. 2002 High

    Identification of Cys-42 as the sole residue mediating HLA-G disulfide-linked dimerization defined a structural feature unique among MHC-I molecules that enhances receptor avidity.

    Evidence Site-directed mutagenesis (Cys42Ser) with surface biotinylation and DTT reduction

    PMID:12454284

    Open questions at the time
    • Whether dimeric HLA-G has differential receptor-binding properties versus monomer not quantified
    • Crystal structure of the dimer not yet available
  9. 2003 High

    Quantitative SPR measurements showing 3–4-fold higher affinity of ILT2 and ILT4 for HLA-G versus classical MHC-I, combined with demonstration that ILT2/ILT4 compete with CD8, established the biophysical basis for preferential immune inhibition by HLA-G.

    Evidence Surface plasmon resonance with recombinant ILT2, ILT4, and multiple MHC-I; CD8 competition assay

    PMID:12853576

    Open questions at the time
    • Structural basis for enhanced affinity not elucidated
    • Impact of dimerization on measured affinities not assessed
  10. 2003 Medium

    The 14-bp insertion polymorphism in the HLA-G 3′ UTR was shown to generate a more stable spliced mRNA, providing a genetic mechanism for inter-individual variation in HLA-G expression levels.

    Evidence Actinomycin D mRNA stability assays in JEG-3 and transfected M8 melanoma cells

    PMID:14602228

    Open questions at the time
    • Whether mRNA stability differences translate to proportional protein-level differences in vivo not demonstrated
    • Trans-acting factors mediating differential stability not identified
  11. 2005 High

    Demonstration that HLA-G/ILT4 engagement arrests DC maturation, disrupts MHC-II presentation, and induces tolerogenic DCs that generate anergic T cells—prolonging allograft survival in ILT4-transgenic mice—linked HLA-G to adaptive immune tolerance induction beyond NK inhibition.

    Evidence Human monocyte-derived DC assays combined with ILT4-transgenic mouse allograft model

    PMID:15770701

    Open questions at the time
    • Intracellular signaling cascade downstream of ILT4 in DCs incompletely defined
    • Whether this pathway functions identically in human tissues in vivo not confirmed
  12. 2007 High

    Soluble HLA-G5 secreted by MSCs in an IL-10-dependent manner was shown to suppress T-cell proliferation and expand FOXP3+ Tregs, extending HLA-G function beyond the trophoblast to MSC-mediated immunomodulation, while soluble HLA-G1 inhibited angiogenesis through CD160 in vitro and in vivo.

    Evidence Anti-HLA-G neutralizing antibody blocking in MSC–T cell cocultures; endothelial cell assays and rabbit corneal neoangiogenesis model with CD160 receptor binding

    PMID:17467060 PMID:17932417

    Open questions at the time
    • Whether HLA-G5 is the principal effector of MSC immunosuppression or one of several redundant mechanisms unknown
    • CD160 signaling pathway downstream of HLA-G binding not fully characterized
  13. 2012 Medium

    The finding that KIR2DL4 resides in endosomes and signals via DNA-PKcs/Akt after capturing soluble HLA-G revealed an unconventional endosomal immune signaling pathway, while LINE1-mediated chromatin silencing upstream of HLA-G added an epigenetic layer of expression control.

    Evidence Endosomal fractionation and kinase pathway analysis for KIR2DL4; human artificial chromosome system with single-copy LINE1 manipulation

    PMID:22934097 PMID:23002136

    Open questions at the time
    • KIR2DL4 endosomal signaling characterized largely from one group; independent replication needed
    • How LINE1 secondary structure recruits silencing factors not defined
  14. 2015 High

    Primary HLA-G+ extravillous trophoblasts were directly shown to expand resting FOXP3+ Tregs in decidual tissue, providing in situ evidence for HLA-G-driven tolerance at the maternal–fetal interface, while DNMT-1-mediated promoter methylation was identified as a mechanism that suppresses HLA-G in preeclampsia.

    Evidence FACS-purified primary EVT coculture with decidual immune cells and microarray profiling; bisulfite pyrosequencing with DNMT-1 siRNA/5-aza-CdR in trophoblast cells

    PMID:26015573 PMID:26116450

    Open questions at the time
    • Whether DNMT-1-mediated silencing is causally linked to preeclampsia pathogenesis or a secondary effect not established
    • Relative contributions of individual immune cell types to Treg expansion not dissected
  15. 2016 High

    CRISPR/Cas9 deletion of Enhancer L (12 kb upstream) ablated HLA-G expression, and chromatin conformation capture showed Enhancer L loops to the promoter via CEBP/GATA factors, resolving the long-standing question of how trophoblast-specific transcription is achieved.

    Evidence MPRA, CRISPR/Cas9 deletion in JEG3 and primary trophoblasts, RNA-seq, DNase-seq, 3C, saturation mutagenesis

    PMID:27078102

    Open questions at the time
    • Whether Enhancer L operates in non-trophoblast contexts (e.g., tumors, MSCs) not tested
    • Complete set of transcription factors required at Enhancer L not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: (1) structural determination of how HLA-G dimers engage ILT2/ILT4 versus KIR2DL4; (2) the in vivo hierarchy among the multiple receptor pathways for maternal–fetal tolerance; (3) whether tumor exploitation of HLA-G recapitulates the same receptor/signaling axis as trophoblast-driven tolerance.
  • No crystal structure of HLA-G dimer–receptor complex available
  • In vivo redundancy among ILT2, ILT4, KIR2DL4, and HLA-E pathways not delineated
  • Relative importance of membrane-bound versus soluble isoforms in tumor immune evasion not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 7 GO:0098631 cell adhesion mediator activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005576 extracellular region 4 GO:0005768 endosome 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-168256 Immune System 10 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 1
Partners
B2MCD160CD8ACD94ILT2ILT4KIR2DL4NKG2A
Complex memberships
HLA-G Cys42-linked homodimerMHC class I/beta2-microglobulin/peptide complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1987 HLA-G (originally designated HLA-6.0) was identified as a non-HLA-A/B/C class I gene encoding a protein with a shortened cytoplasmic segment due to an in-frame stop codon that truncates the majority of the cytoplasmic tail, structurally resembling murine Qa-region class I genes. Genomic cloning, sequencing, and structural analysis Proceedings of the National Academy of Sciences of the United States of America High 3480534
1990 HLA-G protein is expressed as an array of five 37–39 kDa isoforms on first-trimester villous cytotrophoblasts and is greatly reduced in third-trimester cytotrophoblasts; it is not expressed in normal lymphoid cells, demonstrating cell-type-specific and developmental regulation. Two-dimensional gel electrophoresis, immunoprecipitation Science High 2326636
1990 HLA-G encodes a truncated HLA class I heavy chain (~40 kDa) expressed on extravillous trophoblast and the choriocarcinoma cell line BeWo, confirmed by cDNA cloning and sequencing showing high homology to HLA-6.0 genomic clone. cDNA cloning, sequencing, RT-PCR, immunoprecipitation Journal of immunology High 2295808
1992 The HLA-G primary transcript is alternatively spliced to yield at least three distinct mature mRNAs encoding proteins resembling class I (full-length) and truncated forms (lacking alpha2 domain alone, or alpha2+alpha3 domains), with three corresponding protein products detected by immunoprecipitation. RT-PCR, sequencing of alternatively spliced transcripts, immunoprecipitation of [35S]methionine-labeled proteins Proceedings of the National Academy of Sciences of the United States of America High 1570318
1995 HLA-G protein expression is restricted to invasive cytotrophoblasts at the maternal-fetal interface and is up-regulated as cytotrophoblast stem cells differentiate along the invasive pathway in vitro, with term cytotrophoblasts (reduced invasive capacity) showing decreased HLA-G up-regulation. mAb generation using synthetic alpha1-domain peptide, immunoaffinity purification, immunohistochemistry on tissue sections, Northern blot Journal of immunology High 7706718
1996 HLA-G molecules present peptides in a manner analogous to classical HLA molecules; the HLA-G peptide motif is defined as XI/LPXXXXXL with anchor residues at positions 2 (Ile/Leu), 3 (Pro), and 9 (Leu), and peptide-binding assays showed two of three anchors are sufficient for binding. Peptide elution from stably transfected LCL721.221 cells, individual and pool sequencing, peptide-binding assay Current biology High 8805247
1997 Both HLA-G1 (full-length) and HLA-G2 (alpha1+alpha3 truncation) inhibit NK cell cytolysis; HLA-G2 is present at the cell surface associated with beta2-microglobulin; the alpha1 domain shared by G1 and G2 mediates protection from NK lysis; HLA-G was proposed as a 'public ligand' for NK inhibitory receptors. Stable transfection of K562 cells with HLA-G1 or HLA-G2 cDNA, NK cytolysis assay with polyclonal NK cells from 20 donors, mAb blocking Proceedings of the National Academy of Sciences of the United States of America High 9144223
1997 The impaired spontaneous endocytosis of HLA-G is caused by its short cytoplasmic tail; chimeric proteins carrying the HLA-G cytoplasmic tail (or GPI-anchored HLA-C) were not efficiently internalized, demonstrating that the truncated cytoplasmic tail of HLA-G is responsible for its prolonged cell-surface residence. Surface biotinylation, flow cytometric endocytosis assay, beta2-microglobulin exchange labeling with Texas red, chimeric protein constructs European journal of immunology High 9368631
1998 ILT4 (expressed on monocytes, macrophages, and dendritic cells) binds both classical MHC class I molecules and the nonclassical HLA-G, transducing inhibitory signals via immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that recruit phosphatases and suppress early activation signaling in myelomonocytic cells. Receptor characterization by binding assays, ITIM-mediated signaling assay, transfection Journal of immunology High 9531263
1999 Soluble KIR2DL4 binds specifically to cells expressing HLA-G but not to cells expressing other HLA class I molecules; KIR2DL4 is expressed on all NK cells (unlike other clonally distributed KIRs); functional transfer of KIR2DL4 into NK-92 cells inhibits lysis of HLA-G+ targets but not HLA-E+ targets. Recombinant soluble KIR2DL4 binding assay, flow cytometry, functional NK cytotoxicity assay with KIR2DL4 transfectants The Journal of experimental medicine High 10190900
1999 NK recognition of HLA-G1 involves two non-overlapping receptor-ligand systems: (1) direct engagement of ILT2 (LIR1) by HLA-G1, and (2) CD94/NKG2A interaction with HLA-E co-expressed via binding to the nonamer peptide (VMAPRTLFL) from the HLA-G leader sequence. HLA-E-negative mutant transfectants (site-directed mutagenesis of HLA-G leader sequence), ILT2-Ig fusion protein binding assay, mAb blocking of CD94/NKG2A and ILT2 European journal of immunology High 9933109
1999 IL-10 selectively induces HLA-G gene transcription in trophoblasts and up-regulates HLA-G surface expression in peripheral blood monocytes, while simultaneously down-regulating classical MHC class I and MHC class II on monocytes, suggesting IL-10 as a tissue-specific activator of HLA-G expression at the fetal-maternal interface. Northern blot, RNase protection assay, RT-PCR, flow cytometry in trophoblast cultures and monocytes International immunology High 10330285
2000 Soluble HLA-G1 (sHLA-G1) triggers apoptosis in activated (but not resting) CD8+ peripheral blood cells through the CD95/CD95 ligand pathway; sHLA-G1 enhances CD95 ligand expression in activated CD8+ cells; this apoptosis depends on the interaction of sHLA-G1 with CD8 molecules, as CD8-specific mAbs block cell death. Affinity-purified sHLA-G1, Western blotting for CD95L, CD95-Fc and ZB4 blocking experiments, CD8 mAb blocking Journal of immunology High 10843658
2001 HLA-G2, -G3, and -G4 truncated isoforms reach the cell surface as endoglycosidase H-sensitive (immature) glycoproteins and protect transfected cells from both NK and CTL cytolysis, demonstrating that non-G1 membrane-bound isoforms are functional immunomodulatory molecules. Stable transfection, endoglycosidase H sensitivity assay, NK and CTL cytotoxicity assay Journal of immunology High 11290782
2002 HLA-G forms disulfide-linked dimers on the cell surface via a disulfide bond exclusively through Cys-42; mutation of Cys-42 to serine completely abrogates dimerization; the ~78 kDa dimer is reduced to ~39 kDa by DTT. Surface biotinylation, immunoprecipitation with anti-beta2m mAb, DTT reduction, site-directed mutagenesis (Cys42Ser) Proceedings of the National Academy of Sciences of the United States of America High 12454284
2003 ILT2 and ILT4 bind HLA-G with 3- to 4-fold higher affinity than classical MHC class I molecules (KD values measured by surface plasmon resonance); ILT2 binds with 2- to 3-fold higher affinity than ILT4 to the same MHCI; ILT2 and ILT4 compete with CD8 for MHC class I binding. Surface plasmon resonance (SPR) with soluble ILT2 and ILT4 proteins against multiple MHC class I molecules; CD8 competition assay Proceedings of the National Academy of Sciences of the United States of America High 12853576
2003 Melanoma cells release exosomes bearing HLA-G1; these HLA-G1-positive exosomes are also secreted by HLA-G-negative melanoma cells transfected with HLA-G1 cDNA, providing a mechanism for tumor immune modulation via secreted vesicles. Sucrose gradient ultracentrifugation, Western blotting, flow cytometry of purified exosomes Human immunology Medium 14602237
2003 HLA-G1 inhibits NK- and CTL-mediated lysis via ILT2 and ILT4; HLA-G5 (soluble) binds CD8 and induces Fas/FasL-mediated apoptosis in activated CD8+ lymphocytes; KIR2DL4 engagement triggers different responses depending on effector cell activation state. Functional cytotoxicity assays, receptor-ligand characterization Seminars in cancer biology Medium 14708711
2004 Soluble HLA-G1 can be generated by metalloproteinase-dependent shedding of membrane-bound HLA-G1 at the post-translational level; shed sHLA-G1 associates with beta2-microglobulin, contains bound peptides stable at physiological conditions, and protects HLA class I-negative K562 cells from NK lysis. Metalloproteinase inhibitor experiments, Western blotting, NK cytotoxicity assay Biochemical and biophysical research communications Medium 14697234
2005 HLA-G binding to ILT4 on dendritic cells induces tolerogenic DC with arrested maturation/activation; HLA-G-modified DCs induce anergic and immunosuppressive CD4+ and CD8+ T cells; ILT4 ligation on DCs disrupts MHC class II antigen presentation pathway and significantly prolongs allograft survival in ILT4-transgenic mice. Human monocyte-derived DC assays, ILT4-transgenic mouse model, gene expression profiling, allograft survival experiments European journal of immunology High 15770701
2005 Residues Met76 and Gln79 in the alpha1 domain of HLA-G are critical for KIR2DL4 recognition; mutation of these residues to Ala reduces binding of KIR2DL4-IgG Fc fusion protein to HLA-G and alters KIR2DL4-transfected NK-92 cell cytolysis against HLA-G-expressing targets. Retroviral transduction, KIR2DL4-IgG Fc fusion protein binding assay, NK cytotoxicity assay with KIR2DL4-transfected NK-92 cells Cell research Medium 15780179
2007 MSCs secrete the soluble isoform HLA-G5 in an IL-10-dependent manner; cell contact between MSCs and allostimulated T cells is required for full HLA-G5 secretion; blocking HLA-G5 with neutralizing antibody reveals it suppresses allogeneic T-cell proliferation, expands CD4+CD25highFOXP3+ regulatory T cells, inhibits NK-mediated cytolysis, and inhibits IFN-gamma secretion by NK cells. Neutralizing anti-HLA-G antibody blocking, IL-10 pathway inhibition, flow cytometry, cytotoxicity assays Stem cells High 17932417
2010 Tr1 cell differentiation by DC-10 (IL-10-producing tolerogenic DCs that express ILT4 and HLA-G) is IL-10-dependent and requires the ILT4/HLA-G signaling pathway; DC-10 induce antigen-specific IL-10-producing Tr1 cells through this pathway. DC-10 isolation from peripheral blood and in vitro differentiation, Tr1 induction assays, pathway blocking experiments Blood High 20448110
2012 KIR2DL4 resides in endosomes (not on the cell surface like other KIRs); soluble HLA-G accumulates in KIR2DL4+ endosomes; KIR2DL4 signals from this intracellular site for a proinflammatory and proangiogenic response using a novel endosomal signaling pathway involving serine/threonine kinases DNA-PKcs and Akt. Subcellular localization studies, endosomal fractionation, kinase pathway analysis Frontiers in immunology Medium 22934097
2013 Two synthetic HLA-G-derived molecules—(α3-L)x2 and (α1-α3)x2 polypeptides—bind the HLA-G receptor LILRB2; (α1-α3)x2 prolongs allograft survival in mice (one treatment significantly prolongs, four weekly treatments induce complete tolerance) and inhibits tumor cell line proliferation as does full-length HLA-G. Receptor binding assay with LILRB2, in vivo murine skin allograft model, in vitro tumor proliferation assay FASEB journal High 23752205
2015 HLA-G interaction with HLA-G+ extravillous trophoblasts (EVT) and decidual CD4+ T cells results in increased numbers of CD4+CD25hiIFOXP3+CD45RA+ resting regulatory T cells (Tregs) and increased FOXP3 expression, providing a mechanism by which EVT maintain fetal-maternal tolerance. Purification of primary HLA-G+ EVT by FACS, coculture assays with decidual NK cells, macrophages, CD4+ and CD8+ T cells; microarray gene expression analysis; flow cytometry Proceedings of the National Academy of Sciences of the United States of America High 26015573
2016 A trophoblast-specific cis-regulatory enhancer (Enhancer L) located 12 kb upstream of HLA-G controls tissue-specific HLA-G expression; CRISPR/Cas9-mediated deletion of Enhancer L ablates HLA-G expression in JEG3 cells and primary human trophoblasts; Enhancer L loops into the HLA-G promoter via chromatin conformation capture; CEBP and GATA family transcription factors bind Enhancer L and regulate HLA-G expression. Massively parallel reporter assay (MPRA), CRISPR/Cas9 deletion, RNA-seq, DNase-seq, chromatin conformation capture (3C), saturation mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 27078102
2003 The 14 bp insertion polymorphism in the 3' UTR of HLA-G generates an additional splice that removes 92 bases from exon 8; HLA-G mRNAs with this 92-base deletion are more stable than complete mRNA forms, demonstrating that this region controls post-transcriptional regulation of HLA-G expression. Actinomycin D mRNA stability assays in JEG-3 and transfected M8 melanoma cells, RT-PCR Human immunology Medium 14602228
2012 A LINE1 sequence upstream of HLA-G functions as a negative regulator of HLA-G gene expression; HLA-G silencing involves a DNA secondary structure generated within the LINE1 element, as shown by manipulation of a single genomic copy on a human artificial chromosome. Human artificial chromosome system with single-copy genomic manipulation, reporter assays, DNA secondary structure analysis Nucleic acids research Medium 23002136
2015 DNMT-1-mediated promoter hypermethylation suppresses HLA-G expression; CpG sites in the HLA-G promoter are significantly more methylated in preeclampsia; treatment with DNMT inhibitor 5-aza-2'-deoxycytidine or DNMT-1 siRNA knockdown significantly increases HLA-G expression in a trophoblastic cell line. Bisulfite pyrosequencing, siRNA knockdown, 5-aza-2'-deoxycytidine treatment, qPCR, immunohistochemistry Molecular human reproduction Medium 26116450
2007 Soluble HLA-G1 (HLA-G5) inhibits endothelial cell proliferation, migration, and tubule formation through binding to the CD160 receptor via an apoptotic pathway; soluble HLA-G1 also blocks in vivo rabbit corneal neoangiogenesis, demonstrating anti-angiogenic properties. In vitro endothelial cell proliferation, migration and tubule formation assays, CD160 receptor binding, in vivo rabbit corneal neoangiogenesis model Journal of reproductive immunology Medium 17467060

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1990 A class I antigen, HLA-G, expressed in human trophoblasts. Science (New York, N.Y.) 1219 2326636
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1996 Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nature medicine 874 8612235
2007 Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells. Stem cells (Dayton, Ohio) 798 17932417
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1999 A human histocompatibility leukocyte antigen (HLA)-G-specific receptor expressed on all natural killer cells. The Journal of experimental medicine 559 10190900
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
1987 A human major histocompatibility complex class I gene that encodes a protein with a shortened cytoplasmic segment. Proceedings of the National Academy of Sciences of the United States of America 476 3480534
1992 Alternative splicing of HLA-G transcripts yields proteins with primary structures resembling both class I and class II antigens. Proceedings of the National Academy of Sciences of the United States of America 465 1570318
2010 Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. Blood 459 20448110
2003 Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G. Proceedings of the National Academy of Sciences of the United States of America 448 12853576
1998 Human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules. Journal of immunology (Baltimore, Md. : 1950) 430 9531263
1995 Human placental HLA-G expression is restricted to differentiated cytotrophoblasts. Journal of immunology (Baltimore, Md. : 1950) 383 7706718
1998 HLA-G expression in melanoma: a way for tumor cells to escape from immunosurveillance. Proceedings of the National Academy of Sciences of the United States of America 380 9539768
2000 Cutting edge: soluble HLA-G1 triggers CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells by interacting with CD8. Journal of immunology (Baltimore, Md. : 1950) 366 10843658
1990 Human trophoblast and the choriocarcinoma cell line BeWo express a truncated HLA Class I molecule. Journal of immunology (Baltimore, Md. : 1950) 360 2295808
1999 IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes. International immunology 354 10330285
2015 HLA-G: An Immune Checkpoint Molecule. Advances in immunology 327 26073983
2003 The 14 bp deletion-insertion polymorphism in the 3' UT region of the HLA-G gene influences HLA-G mRNA stability. Human immunology 325 14602228
1998 Nef interacts with the mu subunit of clathrin adaptor complexes and reveals a cryptic sorting signal in MHC I molecules. Immunity 325 9586638
2001 Structure--function relationships in HIV-1 Nef. EMBO reports 317 11463741
2007 Allele-specific targeting of microRNAs to HLA-G and risk of asthma. American journal of human genetics 316 17847008
1997 The alpha1 domain of HLA-G1 and HLA-G2 inhibits cytotoxicity induced by natural killer cells: is HLA-G the public ligand for natural killer cell inhibitory receptors? Proceedings of the National Academy of Sciences of the United States of America 315 9144223
2008 HLA-G: from biology to clinical benefits. Trends in immunology 305 18249584
1999 The ILT2(LIR1) and CD94/NKG2A NK cell receptors respectively recognize HLA-G1 and HLA-E molecules co-expressed on target cells. European journal of immunology 300 9933109
2001 HLA-G2, -G3, and -G4 isoforms expressed as nonmature cell surface glycoproteins inhibit NK and antigen-specific CTL cytolysis. Journal of immunology (Baltimore, Md. : 1950) 286 11290782
2008 Beyond the increasing complexity of the immunomodulatory HLA-G molecule. Blood 276 18334671
2010 Implications of the polymorphism of HLA-G on its function, regulation, evolution and disease association. Cellular and molecular life sciences : CMLS 260 21107637
2005 Tolerization of dendritic cells by HLA-G. European journal of immunology 258 15770701
2005 HLA-G in human reproduction: aspects of genetics, function and pregnancy complications. Human reproduction update 226 16280356
2003 Expression of HLA-G in human cornea, an immune-privileged tissue. Human immunology 211 14602233
2002 Disulfide bond-mediated dimerization of HLA-G on the cell surface. Proceedings of the National Academy of Sciences of the United States of America 173 12454284
1996 Nonclassical HLA-G molecules are classical peptide presenters. Current biology : CB 170 8805247
1999 Detection of soluble HLA-G molecules in plasma and amniotic fluid. Tissue antigens 167 10082427
2015 Human HLA-G+ extravillous trophoblasts: Immune-activating cells that interact with decidual leukocytes. Proceedings of the National Academy of Sciences of the United States of America 166 26015573
2008 A critical look at HLA-G. Trends in immunology 160 18538632
2012 The immunosuppressive molecule HLA-G and its clinical implications. Critical reviews in clinical laboratory sciences 151 22537084
2012 KIR2DL4 (CD158d): An activation receptor for HLA-G. Frontiers in immunology 150 22934097
2007 Soluble HLA-G: Are they clinically relevant? Seminars in cancer biology 146 17825579
1999 The functionality of HLA-G is emerging. Immunological reviews 143 10319265
2004 Soluble HLA-G generated by proteolytic shedding inhibits NK-mediated cell lysis. Biochemical and biophysical research communications 139 14697234
2020 Roles of HLA-G in the Maternal-Fetal Immune Microenvironment. Frontiers in immunology 126 33193435
2001 HLA-G genotypes and pregnancy outcome in couples with unexplained recurrent miscarriage. Molecular human reproduction 117 11719594
2018 Heterogeneity of HLA-G Expression in Cancers: Facing the Challenges. Frontiers in immunology 113 30319626
2014 Insights into HLA-G Genetics Provided by Worldwide Haplotype Diversity. Frontiers in immunology 107 25339953
2010 Biology of HLA-G in cancer: a candidate molecule for therapeutic intervention? Cellular and molecular life sciences : CMLS 107 21063893
2003 Exosomes bearing HLA-G are released by melanoma cells. Human immunology 107 14602237
2013 Molecular pathways: human leukocyte antigen G (HLA-G). Clinical cancer research : an official journal of the American Association for Cancer Research 100 23897901
2014 HLA-G Molecules in Autoimmune Diseases and Infections. Frontiers in immunology 98 25477881
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