HLA-G

HLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G (HLA-G), is a protein that in humans is encoded by the HLA-G gene.

HLA-G
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3KYO, 1YDP, 2D31, 2DYP, 3BZE, 3CDG, 3CII, 3KYN
Identifiers
Aliases	HLA-G, MHC-G, major histocompatibility complex, class I, G
External IDs	OMIM: 142871; MGI: 95915; HomoloGene: 133255; GeneCards: HLA-G; OMA:HLA-G - orthologs
Gene location (Human) Chr. Chromosome 6 (human) Band 6p22.1 Start 29,826,967 bp End 29,831,125 bp
Gene location (Mouse) Chr. Chromosome 17 (mouse) Band 17 B1|17 19.16 cM Start 37,581,111 bp End 37,585,375 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in placenta gonad testicle Pituitary Gland anterior pituitary stromal cell of endometrium duodenum rectum blood upper lobe of left lung Top expressed in mesenteric lymph nodes spleen Ileal epithelium aortic valve supraoptic nucleus blood stroma of bone marrow carotid body subcutaneous adipose tissue islet of Langerhans More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein homodimerization activity signaling receptor binding peptide antigen binding protein binding identical protein binding CD8 receptor binding Cellular component integral component of membrane phagocytic vesicle membrane early endosome membrane membrane Golgi membrane MHC class I protein complex ER to Golgi transport vesicle membrane integral component of lumenal side of endoplasmic reticulum membrane recycling endosome membrane extracellular region plasma membrane endosome early endosome endoplasmic reticulum endoplasmic reticulum membrane filopodium membrane cis-Golgi network membrane cell projection extracellular space external side of plasma membrane Biological process antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent positive regulation of tolerance induction positive regulation of interleukin-12 production interferon-gamma-mediated signaling pathway immune system process positive regulation of regulatory T cell differentiation positive regulation of T cell tolerance induction antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-independent cellular defense response negative regulation of T cell proliferation negative regulation of immune response type I interferon signaling pathway regulation of immune response immune response-inhibiting cell surface receptor signaling pathway negative regulation of dendritic cell differentiation antigen processing and presentation of peptide antigen via MHC class I negative regulation of T cell mediated cytotoxicity positive regulation of T cell mediated cytotoxicity peripheral B cell tolerance induction antigen processing and presentation of endogenous peptide antigen via MHC class Ib positive regulation of natural killer cell cytokine production immune response negative regulation of angiogenesis protection from natural killer cell mediated cytotoxicity negative regulation of natural killer cell mediated cytotoxicity negative regulation of protein kinase B signaling positive regulation of macrophage cytokine production protein homotrimerization negative regulation of G0 to G1 transition positive regulation of endothelial cell apoptotic process positive regulation of cellular senescence antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3135 14991 Ensembl ENSG00000230413 ENSG00000233095 ENSG00000237216 ENSG00000276051 ENSG00000204632 ENSG00000235346 ENSG00000235680 ENSG00000206506 ENSMUSG00000016206 UniProt P17693 Q31093 RefSeq (mRNA) NM_002127 NM_001363567 NM_001384280 NM_001384290 NM_013819 RefSeq (protein) NP_002118 NP_001350496 NP_038847 Location (UCSC) Chr 6: 29.83 – 29.83 Mb Chr 17: 37.58 – 37.59 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

HLA-G belongs to the HLA nonclassical class I heavy chain paralogues. Classical HLA I proteins are found on all nucleated cells and express peptides in their peptide binding groove. They can express "self" peptides when the cell is healthy as well as foreign peptides when the cell is infected by a parasite or cancer. HLA-G is a nonclassical protein and serves a different function from classical HLA class I molecules, but it still expresses a nine amino acid peptide in its peptide binding groove. The third and ninth amino acid in the peptide sequence serve as anchor residues, and are thus conserved in all the peptides HLA-G bind to.

Structure

This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-G is coded for by 88 alleles. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exon 6 encodes the cytoplasmic tail. Exon 7 and 8 are not translated due to a stop codon present in exon 6.

HLA-G can be expressed under at least seven isoforms through alternative splicing, called HLA-G1, HLA-G2,..., HLA-G7. The protein can be both membrane-bound and soluble. HLA-G1 through G4 are membrane bound and HLA-G5 through G7 are soluble. HLA-G1 and HLA-G5 are the most studied isoforms due to the wider availability of antibodies _targeting them. HLA-G can present a more narrow variety of peptides than its classical HLA class I counterparts due to it having a more limited polymorphism.

Function

In the Human Body

HLA-G is a major immune checkpoint, meaning it downregulates the immune system's response. Soluble HLA-G can be found in the saliva, ascitic fluid, plasma, thymus, seminal plasma, cerebrospinal fluid, and in first and second term placentas. Membrane-bound HLA-G is predominantly found on trophoblast cells in the placenta, but it is also found in the thymus, cornea, erythroblasts, and mesenchymal stem cells. It can be upregulated in cancers. Peptides are connected to HLA-G by the peptide loading complex in the endoplasmic reticulum.

Pregnancy

HLA-G plays a role in immune tolerance in pregnancy, being expressed in the placenta by extravillous trophoblast cells (EVT), while the classical MHC class I genes (HLA-A and HLA-B) are not. As HLA-G was first identified in placenta samples, many studies have evaluated its role in pregnancy disorders, such as preeclampsia and recurrent pregnancy loss. Its downregulation is related to HLA-A and -B downregulation results in protection from cytotoxic T cell responses, but would in theory result in a missing self response by natural killer cells. HLA-G is a ligand for natural killer (NK) cell inhibitory receptor KIR2DL4, and therefore expression of this HLA by the trophoblast defends it against NK cell-mediated death.

The presence of soluble HLA-G (sHLA-G) in embryos is associated with better pregnancy rates. In order to optimize pregnancy rates, there is significant evidence that a morphological scoring system is the best strategy for the selection of embryos. However, presence of soluble HLA-G might be considered as a second parameter if a choice has to be made between embryos of morphologically equal quality.

Parasitic Infections

HLA-G has been shown to modulate the body's response to parasitic diseases. Recent studies have emerged suggesting a link between HLA-G and P. falciparum, which is one of the most dangerous malaria strains. In pregnant women, P. falciparum can infect the placenta, causing low birth weights and other complications. High levels of soluble HLA-G have been linked to higher instances of low birth weights. There is also a link between HLA-G expression and Human African trypanosomiasis (HAT). People with higher levels of soluble HLA-G are more likely to be diagnosed with the disease. There may also be genetic differences driving the instance and severity of HAT, as a few single nucleotide polymorphisms have been associated with higher levels of HAT. There is also an effect in Toxoplasmosis infections in pregnant women, where HLA-G is upregulated to protect the fetus from inflammation. Treatment of cells with IL-10 leads to a downregulation of HLA-G, which could be an avenue for therapy in instances where too much HLA-G is produced. Individuals with Visceral leishmaniasis infections also have higher levels of soluble HLA-G, which may be due to a strategy by Leishmania to evade the immune system.

Cancer

HLA-G has been shown to be associated with tumor escape in cancers, because it causes the immune system to not pay attention to cancer cells. Because it is upregulated in cancer cells, it could serve as a potential _target for immunotherapy. Monoclonal antibodies that bind to HLA-G have been used successfully against cancers as part of a strategy to inhibit immune checkpoints. HLA-G has potential utility as a tumor marker due to the large increase in HLA-G in many cancers, including breast cancer, ovarian cancer, and lung cancer. Increased expression of HLA-G has been associated with the metastatic potential of tumor cells.

Allergy

HLA-G has links to allergenic responses in the body. Soluble HLA-G levels are higher in the serum of people with allergic rhinitis, or hay fever. Additionally, single nucleotide polymorphisms in HLA-G have been connected to an increased likelihood of having asthma. Papillary cells expressing HLA-G were found in patients with atopic dermatitis.

Interactions

HLA-G has been shown to interact with CD8A. When in its soluble form, HLA-G interacts with Ig-like transcript 2 (ILT2), a leukocyte receptor. When it’s membrane bound, it interacts with Ig-like transcript 4 (ILT4). Soluble HLA-G can bind to KIR2DL4, which is often found on the surface of natural killer cells. The identity of the peptide presented by HLA-G is unrelated to the binding of HLA with KIR2DL4, ILT2, or ILT4. Because HLA-G interacts with receptors using a variety of its domains, multiple antibodies are necessary to inhibit all of its functions.

Both ILT2 and ILT4 cause negative intracellular signaling. In monocytes, binding to either ILT2 or ILT4 receptors cause the inhibition of monocyte/macrophage mediated toxicity. In dendritic cells, binding to both receptors can prevent dendritic cells from maturing and prevent the activation of T cells. Additionally, HLA-G may interact with ILT4 receptors on the surface of neutrophils to inhibit phagocytosis. In natural killer cells, HLA-G binds with the ILT2 receptor to inhibit the secretion of IFN-γ, a cytokine that can activate macrophages and stimulate natural killer cells and neutrophils. HLA-G binds to ILT2 on B cells to cause the inhibition of B cell proliferation, differentiation, and the secretion of antibodies. It binds to ILT2 on T cells to downregulate T cell chemokine expression. The cytokine expression of T cells mimics that of T_H2 cells. HLA-G causes apoptosis in CD8+ T cells. All together these effects serve to decrease the inflammatory response of the immune system.

HLA-G as a Clinical _target

Immune Checkpoint Inhibitors

Because of HLA-G's role in inhibiting NK cell responses in cancer, clinical immune checkpoint inhibitors _targeting HLA-G have been designed. Tizona Therapeutics developed TTX-080, a monoclonal antibody _targeting HLA-G's interaction with ILT2 and ILT4. In 2020, a phase 1a/1b trial began to assess safety and preliminary efficacy in multiple cancers. Early results showed activity in HPV-negative HNSCC and HER2-negative metastatic colorectal cancer with WT RAS/BRAF, leading to an expansion of the trial.

CAR T-cell Therapy

HLA-G is both an immune checkpoint and a tumor-specific antigen, making it a _target for the development of CAR T-cell therapies, which have been shown to have efficacy in in vitro mouse models. The company Invectys developed the CAR T-cell therapy IVS-3001 _targeting HLA-G and began Phase1\2a clinical trials June 2023. Based on preliminary results, IVS-3001 was granted FDA fast track designation, expediting development and review of the therapy for potential use in patients with renal cell carcinoma (RCC).

Further reading

• Carosella ED, Favier B, Rouas-Freiss N, Moreau P, Lemaoult J (May 2008). "Beyond the increasing complexity of the immunomodulatory HLA-G molecule". Blood. 111 (10): 4862–4870. doi:10.1182/blood-2007-12-127662. PMID 18334671. S2CID 19170578.
• Carosella ED, Moreau P, Lemaoult J, Rouas-Freiss N (March 2008). "HLA-G: from biology to clinical benefits". Trends in Immunology. 29 (3): 125–132. doi:10.1016/j.it.2007.11.005. PMID 18249584.
• Arnaiz-Villena A, Martinez-Laso J, Alvarez M, Castro MJ, Varela P, Gomez-Casado E, et al. (1997). "Primate Mhc-E and -G alleles". Immunogenetics. 46 (4): 251–266. doi:10.1007/s002510050271. PMID 9218527. S2CID 2918451.
• Le Bouteiller P (February 2000). "HLA-G in the human placenta: expression and potential functions". Biochemical Society Transactions. 28 (2): 208–212. doi:10.1042/bst0280208. PMID 10816129.
• Geyer M, Fackler OT, Peterlin BM (July 2001). "Structure--function relationships in HIV-1 Nef". EMBO Reports. 2 (7): 580–585. doi:10.1093/embo-reports/kve141. PMC 1083955. PMID 11463741.
• Langat DK, Hunt JS (November 2002). "Do nonhuman primates comprise appropriate experimental models for studying the function of human leukocyte antigen-G?". Biology of Reproduction. 67 (5): 1367–1374. doi:10.1095/biolreprod.102.005587. PMID 12390864.
• Moreau P, Dausset J, Carosella ED, Rouas-Freiss N (November 2002). "Viewpoint on the functionality of the human leukocyte antigen-G null allele at the fetal-maternal interface". Biology of Reproduction. 67 (5): 1375–1378. doi:10.1095/biolreprod.102.005439. PMID 12390865.
• Moreau P, Rousseau P, Rouas-Freiss N, Le Discorde M, Dausset J, Carosella ED (September 2002). "HLA-G protein processing and transport to the cell surface". Cellular and Molecular Life Sciences. 59 (9): 1460–1466. doi:10.1007/s00018-002-8521-8. PMC 11337420. PMID 12440768. S2CID 9352496.
• Greenway AL, Holloway G, McPhee DA, Ellis P, Cornall A, Lidman M (April 2003). "HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication". Journal of Biosciences. 28 (3): 323–335. doi:10.1007/BF02970151. PMID 12734410. S2CID 33749514.
• Bénichou S, Benmerah A (January 2003). "[The HIV nef and the Kaposi-sarcoma-associated virus K3/K5 proteins: "parasites"of the endocytosis pathway]". Médecine/Sciences. 19 (1): 100–106. doi:10.1051/medsci/2003191100. PMID 12836198.
• Le Bouteiller P, Legrand-Abravanel F, Solier C (April 2003). "Soluble HLA-G1 at the materno-foetal interface--a review". Placenta. 24 (Suppl A): S10–S15. doi:10.1053/plac.2002.0931. PMID 12842408.
• Sköld M, Behar SM (October 2003). "Role of CD1d-restricted NKT cells in microbial immunity". Infection and Immunity. 71 (10): 5447–5455. doi:10.1128/IAI.71.10.5447-5455.2003. PMC 201095. PMID 14500461.
• Wiendl H, Mitsdoerffer M, Weller M (November 2003). "Express and protect yourself: the potential role of HLA-G on muscle cells and in inflammatory myopathies". Human Immunology. 64 (11): 1050–1056. doi:10.1016/j.humimm.2003.07.001. PMID 14602235.
• Urosevic M, Dummer R (November 2003). "HLA-G in skin cancer: a wolf in sheep's clothing?". Human Immunology. 64 (11): 1073–1080. doi:10.1016/j.humimm.2003.08.351. PMID 14602238.
• Carosella ED, Moreau P, Le Maoult J, et al. (2003). HLA-G Molecules: From Maternal–Fetal Tolerance to Tissue Acceptance. Advances in Immunology. Vol. 81. pp. 199–252. doi:10.1016/S0065-2776(03)81006-4. ISBN 978-0-12-022481-4. PMID 14711057.
• Leavitt SA, SchOn A, Klein JC, Manjappara U, Chaiken IM, Freire E (February 2004). "Interactions of HIV-1 proteins gp120 and Nef with cellular partners define a novel allosteric paradigm". Current Protein & Peptide Science. 5 (1): 1–8. doi:10.2174/1389203043486955. PMID 14965316.
• Le Maoult J, Rouas-Freiss N, Le Discorde M, Moreau P, Carosella ED (March 2004). "[HLA-G in organ transplantation]". Pathologie-Biologie. 52 (2): 97–103. doi:10.1016/j.patbio.2003.04.006. PMID 15001239.
• Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M (April 2004). "HIV/SIV escape from immune surveillance: focus on Nef". Current HIV Research. 2 (2): 141–151. doi:10.2174/1570162043484924. PMID 15078178.
• Joseph AM, Kumar M, Mitra D (January 2005). "Nef: "necessary and enforcing factor" in HIV infection". Current HIV Research. 3 (1): 87–94. doi:10.2174/1570162052773013. PMID 15638726.
• McIntire RH, Hunt JS (April 2005). "Antigen presenting cells and HLA-G--a review". Placenta. 26 (Suppl A): S104–S109. doi:10.1016/j.placenta.2005.01.006. PMID 15837058.
• Anderson JL, Hope TJ (April 2004). "HIV accessory proteins and surviving the host cell". Current HIV/AIDS Reports. 1 (1): 47–53. doi:10.1007/s11904-004-0007-x. PMID 16091223. S2CID 34731265.