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Gene Review

HLA-G  -  major histocompatibility complex, class I, G

Homo sapiens

Synonyms: HLA G antigen, HLA class I histocompatibility antigen, alpha chain G, HLA-6.0, HLAG, MHC class I antigen G
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Disease relevance of HLA-G

  • It is of note that CD56+CD4+ lymphomas displayed stronger HLA-G reactivity [1].
  • The aim of this study was to assess the expression of nonclassical HLA-G antigens in ex vivo human melanoma biopsies [2].
  • High levels of HLA-G transcription were detected in tumor specimens in 5 of 23 patients and found to be comparable in both lymph node and skin metastases [2].
  • HLA-G expression was here investigated on paraffin-embedded tumor and adjacent normal renal tissues of 18 renal cell carcinoma (RCC) patients [3].
  • PBL and isolated gammadelta T cells from healthy pregnant women as well as from those at risk for premature pregnancy termination were conjugated to choriocarcinoma cells (JAR) transfected with nonclassical HLA Ags (HLA-E, HLA-G) [4].
  • This contribution reviews the HLA-G expression pattern in malignant melanoma lesions, its correlation to the loss of classical HLA class I antigens, and new aspects of HLA-G regulation [5].
  • HLA-G seems to contribute to the impaired immune response in B-CLL supporting disease progression [6].

Psychiatry related information on HLA-G


High impact information on HLA-G

  • The expressed MHC class I genes of this species are more closely related to the human non-classical HLA-G gene than they are to genes of the human classical HLA-A, -B, and -C loci [9].
  • We review these points, with special emphasis on the role of HLA-G in human pathologies, such as cancer, viral infection, and inflammatory diseases, as well as in organ transplantation [10].
  • However, trophoblast cells directly in contact with the maternal tissues express the class I molecule HLA-G, which may be involved in protecting the trophoblast from recognition by NK cells [11].
  • The receptors on NK cells that recognize HLA-G are also identified [11].
  • Here evidence is provided that expression of HLA-G is sufficient to protect otherwise susceptible target cells from lysis by activated NK1 and NK2 cell lines and clones that are specific for distinct groups of HLA-C alleles [11].

Chemical compound and disease context of HLA-G


Biological context of HLA-G

  • 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 [15].
  • Here, we describe the partial inhibition of NK lysis of the MHC class I negative cell line LCL721.221 upon HLA-G transfection [15].
  • This region appears to be deleted in certain HLA haplotypes, shortening the distance between HLA-A and HLA-G by greater than 50 kilobase pairs (kbp) [16].
  • Using probes derived from the ends of YAC inserts and from class I pseudogenes, we describe a highly polymorphic region between the HLA-A and HLA-G genes [16].
  • Disulfide bond-mediated dimerization of HLA-G on the cell surface [17].

Anatomical context of HLA-G

  • In contrast, HLA-G tetramers did bind to peripheral blood monocytes, staining a CD16(+)CD14(mid) subset with greater intensity [18].
  • Primary cutaneous CD8+ and CD56+ T-cell lymphomas express HLA-G and killer-cell inhibitory ligand, ILT2 [1].
  • We also demonstrated that HLA-G cell surface expression and secretion is maintained in a tumor cell line (DM) established from an HLA-G-positive RCC lesion [3].
  • Further, HLA-G reduced alloproliferation, interfered with effective priming of antigen-specific cytotoxic T cells and reduced antigen-specific alloreactive lysis [19].
  • Complexes of HLA-G protein on the cell surface are important for leukocyte Ig-like receptor-1 function [20].

Associations of HLA-G with chemical compounds

  • Mutation of Cys-42 to a serine completely abrogated dimerization of HLA-G, suggesting that the disulfide linkage formed exclusively through this residue [17].
  • Immunoprecipitation experiments demonstrated the involvement of the cysteine residues in the formation of HLA-G protein oligomers on the cell surface [20].
  • HLA-G binds nonamer peptides with leucine or isoleucine at position 2, proline at position 3 and leucine at position 9 [21].
  • Peptides presented by HLA-G usually consisted of 9 amino acids, and adhered to a specific sequence motif, with anchor residues at position 2 (isoleucine or leucine), position 3 (proline) and the carboxy-terminal position 9 (leucine) [22].
  • Removal of polylactosamine chains by endo-beta D-galactosidase digestion significantly reduced the electrophoretic mobility of the immunoreactive bands, suggesting that HLA-G, unlike class Ib molecules studied to date, carries N-acetyllactosamine units [23].

Physical interactions of HLA-G

  • These results suggest that subtle structural differences between LILRB family members cause the distinct binding specificities to various forms of HLA-G and other MHCIs, which may in turn regulate immune suppression [24].
  • In addition, the HLA-G gene provides a suitable leader sequence peptide capable of binding to HLA-E [25].
  • These HLA-G tetramers failed to bind to NK cells and cells transfected with CD94/NKG2 and killer immunoglobulin-like NK receptors [18].
  • However, staining in the presence of antibodies reactive with ILT receptors revealed that the interaction of HLA-G tetramers with blood monocytes was largely due to binding to ILT4 [18].
  • In this report, we demonstrate that CD8 can bind to HLA-G [26].

Regulatory relationships of HLA-G

  • Here we show that recombinant soluble KIR2DL4 binds to cells expressing HLA-G but not to cells expressing other HLA class I molecules [27].
  • Previous studies using human 721.221 cell line have shown that peptides derived from the leader sequence of the HLA-G binds and up-regulates the surface expression of HLA-E molecules, which was considered to consequently provide negative signals to human NK cells [28].
  • Accordingly, the aim of this study was to define the behavior of HLA-G once it is co-expressed into an HLA-A, -B, -C and -E+ cell line [29].
  • The formation of these complexes on the cell surface might represent a novel mechanism developed specifically by the HLA-G protein aimed to control the efficiency of the CD85J/LIR-1-mediated inhibition [30].
  • In addition, while HLA-G-expressing transfectants of LCL.721.221 cells are protected from lymphokine-activated killer lysis, extravillous cytotrophoblast cells and HLA-G-expressing choriocarcinoma cells (CC) are not [31].

Other interactions of HLA-G

  • Therefore, given that HLA-G expression is restricted to fetal trophoblast cells, KIR2DL4 may provide important signals to maternal NK decidual cells that interact with trophoblast cells at the maternal-fetal interface during pregnancy [27].
  • An extensive network of contacts between the peptide and the antigen-binding cleft reveal a constrained mode of binding reminiscent of the nonclassical HLA-E molecule, thereby providing a structural basis for the limited peptide repertoire of HLA-G [32].
  • LILRB2 exhibits an overlapping but distinct MHCI recognition mode compared with LILRB1 and dominantly recognizes the hydrophobic site of the HLA-G alpha3 domain [24].
  • Both HLA-E and HLA-G bind peptides and are involved in natural killer (NK)-cell recognition, but the role of HLA-F is unclear [21].
  • In humans, expression of the highly polymorphic classical HLA-A and HLA-B loci is suppressed, while expression of the nonclassical HLA-G locus is up-regulated at the maternal-fetal interface [33].

Analytical, diagnostic and therapeutic context of HLA-G


  1. Primary cutaneous CD8+ and CD56+ T-cell lymphomas express HLA-G and killer-cell inhibitory ligand, ILT2. Urosevic, M., Kamarashev, J., Burg, G., Dummer, R. Blood (2004) [Pubmed]
  2. Heterogeneity of HLA-G gene transcription and protein expression in malignant melanoma biopsies. Paul, P., Cabestré, F.A., Le Gal, F.A., Khalil-Daher, I., Le Danff, C., Schmid, M., Mercier, S., Avril, M.F., Dausset, J., Guillet, J.G., Carosella, E.D. Cancer Res. (1999) [Pubmed]
  3. Tumor-specific up-regulation of the nonclassical class I HLA-G antigen expression in renal carcinoma. Ibrahim, E.C., Guerra, N., Lacombe, M.J., Angevin, E., Chouaib, S., Carosella, E.D., Caignard, A., Paul, P. Cancer Res. (2001) [Pubmed]
  4. Recognition of nonclassical HLA class I antigens by gamma delta T cells during pregnancy. Barakonyi, A., Kovacs, K.T., Miko, E., Szereday, L., Varga, P., Szekeres-Bartho, J. J. Immunol. (2002) [Pubmed]
  5. HLA-G expression in malignant melanoma. Rebmann, V., Wagner, S., Grosse-Wilde, H. Semin. Cancer Biol. (2007) [Pubmed]
  6. HLA-G in B-chronic lymphocytic leukaemia: clinical relevance and functional implications. Rebmann, V., Nückel, H., Dührsen, U., Grosse-Wilde, H. Semin. Cancer Biol. (2007) [Pubmed]
  7. HLA-G expression during preimplantation human embryo development. Jurisicova, A., Casper, R.F., MacLusky, N.J., Mills, G.B., Librach, C.L. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  8. Expression of the immune-tolerogenic major histocompatibility molecule HLA-G in multiple sclerosis: implications for CNS immunity. Wiendl, H., Feger, U., Mittelbronn, M., Jack, C., Schreiner, B., Stadelmann, C., Antel, J., Brueck, W., Meyermann, R., Bar-Or, A., Kieseier, B.C., Weller, M. Brain (2005) [Pubmed]
  9. Evolution of the MHC class I genes of a New World primate from ancestral homologues of human non-classical genes. Watkins, D.I., Chen, Z.W., Hughes, A.L., Evans, M.G., Tedder, T.F., Letvin, N.L. Nature (1990) [Pubmed]
  10. HLA-G molecules: from maternal-fetal tolerance to tissue acceptance. Carosella, E.D., Moreau, P., Le Maoult, J., Le Discorde, M., Dausset, J., Rouas-Freiss, N. Adv. Immunol. (2003) [Pubmed]
  11. Protection from natural killer cell-mediated lysis by HLA-G expression on target cells. Pazmany, L., Mandelboim, O., Valés-Gómez, M., Davis, D.M., Reyburn, H.T., Strominger, J.L. Science (1996) [Pubmed]
  12. The 14 bp deletion-insertion polymorphism in the 3' UT region of the HLA-G gene influences HLA-G mRNA stability. Rousseau, P., Le Discorde, M., Mouillot, G., Marcou, C., Carosella, E.D., Moreau, P. Hum. Immunol. (2003) [Pubmed]
  13. Progesterone enhances HLA-G gene expression in JEG-3 choriocarcinoma cells and human cytotrophoblasts in vitro. Yie, S.M., Li, L.H., Li, G.M., Xiao, R., Librach, C.L. Hum. Reprod. (2006) [Pubmed]
  14. Induction of HLA-G expression in a melanoma cell line OCM-1A following the treatment with 5-aza-2'-deoxycytidine. Yan, W.H., Lin, A.F., Chang, C.C., Ferrone, S. Cell Res. (2005) [Pubmed]
  15. Human histocompatibility leukocyte antigen (HLA)-G molecules inhibit NKAT3 expressing natural killer cells. Münz, C., Holmes, N., King, A., Loke, Y.W., Colonna, M., Schild, H., Rammensee, H.G. J. Exp. Med. (1997) [Pubmed]
  16. Cloning and physical mapping of the HLA class I region spanning the HLA-E-to-HLA-F interval by using yeast artificial chromosomes. Geraghty, D.E., Pei, J., Lipsky, B., Hansen, J.A., Taillon-Miller, P., Bronson, S.K., Chaplin, D.D. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  17. Disulfide bond-mediated dimerization of HLA-G on the cell surface. Boyson, J.E., Erskine, R., Whitman, M.C., Chiu, M., Lau, J.M., Koopman, L.A., Valter, M.M., Angelisova, P., Horejsi, V., Strominger, J.L. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  18. Tetrameric complexes of human histocompatibility leukocyte antigen (HLA)-G bind to peripheral blood myelomonocytic cells. Allan, D.S., Colonna, M., Lanier, L.L., Churakova, T.D., Abrams, J.S., Ellis, S.A., McMichael, A.J., Braud, V.M. J. Exp. Med. (1999) [Pubmed]
  19. The non-classical MHC molecule HLA-G protects human muscle cells from immune-mediated lysis: implications for myoblast transplantation and gene therapy. Wiendl, H., Mitsdoerffer, M., Hofmeister, V., Wischhusen, J., Weiss, E.H., Dichgans, J., Lochmuller, H., Hohlfeld, R., Melms, A., Weller, M. Brain (2003) [Pubmed]
  20. Complexes of HLA-G protein on the cell surface are important for leukocyte Ig-like receptor-1 function. Gonen-Gross, T., Achdout, H., Gazit, R., Hanna, J., Mizrahi, S., Markel, G., Goldman-Wohl, D., Yagel, S., Horejsí, V., Levy, O., Baniyash, M., Mandelboim, O. J. Immunol. (2003) [Pubmed]
  21. Structure and function of the human MHC class Ib molecules HLA-E, HLA-F and HLA-G. O'Callaghan, C.A., Bell, J.I. Immunol. Rev. (1998) [Pubmed]
  22. Nonclassical HLA-G molecules are classical peptide presenters. Diehl, M., Münz, C., Keilholz, W., Stevanović, S., Holmes, N., Loke, Y.W., Rammensee, H.G. Curr. Biol. (1996) [Pubmed]
  23. HLA-G isoforms produced by placental cytotrophoblasts and found in amniotic fluid are due to unusual glycosylation. McMaster, M., Zhou, Y., Shorter, S., Kapasi, K., Geraghty, D., Lim, K.H., Fisher, S. J. Immunol. (1998) [Pubmed]
  24. Structural basis for recognition of the nonclassical MHC molecule HLA-G by the leukocyte Ig-like receptor B2 (LILRB2/LIR2/ILT4/CD85d). Shiroishi, M., Kuroki, K., Rasubala, L., Tsumoto, K., Kumagai, I., Kurimoto, E., Kato, K., Kohda, D., Maenaka, K. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  25. The HLA-G*0105N null allele induces cell surface expression of HLA-E molecule and promotes CD94/NKG2A-mediated recognition in JAR choriocarcinoma cell line. Sala, F.G., Del Moral, P.M., Pizzato, N., Legrand-Abravanel, F., Le Bouteiller, P., Lenfant, F. Immunogenetics (2004) [Pubmed]
  26. Cell-cell adhesion mediated by CD8 and human histocompatibility leukocyte antigen G, a nonclassical major histocompatibility complex class 1 molecule on cytotrophoblasts. Sanders, S.K., Giblin, P.A., Kavathas, P. J. Exp. Med. (1991) [Pubmed]
  27. A human histocompatibility leukocyte antigen (HLA)-G-specific receptor expressed on all natural killer cells. Rajagopalan, S., Long, E.O. J. Exp. Med. (1999) [Pubmed]
  28. HLA-E and HLA-G expression on porcine endothelial cells inhibit xenoreactive human NK cells through CD94/NKG2-dependent and -independent pathways. Sasaki, H., Xu, X.C., Mohanakumar, T. J. Immunol. (1999) [Pubmed]
  29. HLA-G1 co-expression boosts the HLA class I-mediated NK lysis inhibition. Riteau, B., Menier, C., Khalil-Daher, I., Martinozzi, S., Pla, M., Dausset, J., Carosella, E.D., Rouas-Freiss, N. Int. Immunol. (2001) [Pubmed]
  30. The CD85J/leukocyte inhibitory receptor-1 distinguishes between conformed and beta 2-microglobulin-free HLA-G molecules. Gonen-Gross, T., Achdout, H., Arnon, T.I., Gazit, R., Stern, N., Horejsí, V., Goldman-Wohl, D., Yagel, S., Mandelboim, O. J. Immunol. (2005) [Pubmed]
  31. Trophoblast cell line resistance to NK lysis mainly involves an HLA class I-independent mechanism. Avril, T., Jarousseau, A.C., Watier, H., Boucraut, J., Le Bouteiller, P., Bardos, P., Thibault, G. J. Immunol. (1999) [Pubmed]
  32. Crystal structure of HLA-G: a nonclassical MHC class I molecule expressed at the fetal-maternal interface. Clements, C.S., Kjer-Nielsen, L., Kostenko, L., Hoare, H.L., Dunstone, M.A., Moses, E., Freed, K., Brooks, A.G., Rossjohn, J., McCluskey, J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  33. Identification of a novel MHC class I gene, Mamu-AG, expressed in the placenta of a primate with an inactivated G locus. Boyson, J.E., Iwanaga, K.K., Golos, T.G., Watkins, D.I. J. Immunol. (1997) [Pubmed]
  34. Evidence of balancing selection at the HLA-G promoter region. Tan, Z., Shon, A.M., Ober, C. Hum. Mol. Genet. (2005) [Pubmed]
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