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Gene Review

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

Homo sapiens

Synonyms: EA1.2, EA2.1, HLA class I histocompatibility antigen, alpha chain E, HLA-6.2, HLAE, ...
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Disease relevance of HLA-E

  • We then identify the residues in HLA-C and HLA-E that protect them from HIV down-regulation [1].
  • We present evidence that HIV-1 selectively downregulates HLA-A and HLA-B but does not significantly affect HLA-C or HLA-E [1].
  • Human cytomegalovirus (HCMV) infection as well as the HLA-E and killer immunoglobulin-like receptor (KIR) genotypes were considered as potentially relevant variables associated with CD94/NKG2C expression [2].
  • Importantly, HLA-E tetramer-positive or NKG2A+ T cells from HTLV-1 patients do not express Tax and display different TCR usage from the immunodominant Tax11-19-specific CD8+ T cells, suggesting that they do not encounter HTLV-1-infected cells [3].
  • Finally, HLA-E expression at the cell surface of melanoma cells decreased their susceptibility to CTL lysis [4].

Psychiatry related information on HLA-E


High impact information on HLA-E

  • MHC tetramers, intracellular cytokine staining, an increasing repertoire of transgenic and "knockout" mice, and the detailed characterization of a variety of infectious models have all facilitated more precise and definitive analyses of the generation and function of cytotoxic T lymphocytes (CTL) [10].
  • The conversion of exogenous and endogenous proteins into immunogenic peptides recognized by T lymphocytes involves a series of proteolytic and other enzymatic events culminating in the formation of peptides bound to MHC class I or class II molecules [11].
  • The recognition of peptide MHC class II complexes on activated antigen-presenting cells is critical for effective Th cell selection, clonal expansion, and effector Th cell function development (Phase I) [12].
  • Human vascular endothelial cells (EC) basally display class I and II MHC-peptide complexes on their surface and come in regular contact with circulating T cells [13].
  • Their deaths are prevented in animals by IL-7 and contact with MHC [14].

Chemical compound and disease context of HLA-E


Biological context of HLA-E


Anatomical context of HLA-E

  • Pulse chase experiments revealed that the HLA-E heavy chain in transfectants, obtained with the murine myeloma cell line P3X63-Ag8.653 (X63), displays a significant reduction in oligosaccharide maturation and intracellular transport compared with HLA-B27 in corresponding transfectants [23].
  • Selective expansion of intraepithelial lymphocytes expressing the HLA-E-specific natural killer receptor CD94 in celiac disease [25].
  • HLA-E had no apparent inhibitory effect mediated through the identified Ig superfamily (Ig-SF) human killer cell inhibitory receptors or ILT2/LIR1 [26].
  • The human major histocompatibility complex (MHC) class Ib gene, HLA-E, codes for the major ligand of the inhibitory receptor NK-G-2A, which is present on most natural killer (NK) cells and some CD8(+) cytotoxic T lymphocytes [27].
  • In line with these in vitro data we found enhanced intrahepatic HLA-E expression on antigen-presenting cells in HCV-infected patients [28].

Associations of HLA-E with chemical compounds

  • Signal peptides derived from certain HLA-B proteins with threonine in position 2 only marginally up-regulated HLA-E surface expression in .221 cells [29].
  • Peptides bound to HLA-E consisted of nine amino acids, with methionine at position 2 and leucine in the carboxyl-terminal position, and were nearly identical to the leader sequence-derived peptide previously shown to be a predominant peptide bound to the murine Qa-1 Ag [29].
  • The replacement substitution changes an arginine to a glycine at position 107, defining two alleles at the HLA-E locus [30].
  • We first demonstrated the role of DNA methylation in the repression of class I genes (except HLA-E) in JAR by the use of the 5-Azacytidine demethylating agent [31].
  • Extended MHC haplotypes and CYP21/C4 gene organisation in Irish 21-hydroxylase deficiency families [32].

Physical interactions of HLA-E

  • Thus, during cellular stress an increased proportion of HLA-E molecules may bind the nonprotective hsp60 signal peptide, leading to a reduced capacity to inhibit a major NK cell population [33].
  • HLA-E presents closely related nonameric peptide epitopes derived from the highly conserved signal sequences of classical major histocompatibility complex class I molecules as well as HLA-G [34].
  • Furthermore, we show that the vast majority of decidual NK cells bind to HLA-E tetrameric complexes and this binding is inhibited by mAb to CD94 [35].
  • We now show that the extracellular region of HLA-E forms a stable complex with beta2 microglobulin and can be refolded around synthetic peptide [36].
  • CD94-T4/NKG2B is capable of binding HLA-E and, when expressed in E6-1 Jurkat T cells, inhibits TCR mediated signals, demonstrating that this heterodimer is functional [37].

Regulatory relationships of HLA-E

  • 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 [38].
  • The CD94/NKG2C heterodimer constitutes an activating receptor involved in NK cell-mediated recognition of the class lb molecule HLA-E [39].
  • The aberrant HLA-E expression might be of particular biological relevance in those HLA tumor phenotypes that express a single HLA-A allele when NK inhibition is markedly reduced due to the downregulation of HLA-B and -C alleles [40].
  • In contrast, co-culture of LGL with HLA-E-expressing cells significantly (P < 0.01) decreased only IL-10 production, although a strong tendency towards reduced IL-13 levels was also observed [41].
  • To investigate the involvement of killer-inhibitory/killer-activatory receptors in trophoblast recognition, we tested the effect of CD94 block on cytotoxic activity of Vdelta2(+) enriched gammadelta T cells to HLA-E- and/or HLA-G-transfected targets [42].

Other interactions of HLA-E

  • The third expressed non-A, -B, and -C class I gene, HLA-E, is located between HLA-A and HLA-C (4) [43].
  • This peptide gains access to HLA-E intracellularly, resulting in up-regulated HLA-E/hsp60 signal peptide cell-surface levels on stressed cells [33].
  • Furthermore, functional transfer of KIR2DL4 into the cell line NK-92 resulted in inhibition of lysis of target cells that express HLA-G, but not target cells that express other class I molecules including HLA-E [44].
  • HLA-G and HLA-E: fundamental and pathophysiological aspects [45].
  • One of the most important of these mechanisms of regulation is the recognition of the non-classical class I MHC molecule HLA-E, in complex with nonamer peptides derived from the signal sequences of certain class I MHC molecules, by heterodimers of the C-type lectin-like proteins CD94 and NKG2 [46].

Analytical, diagnostic and therapeutic context of HLA-E

  • To analyze whether HLA-E binds peptides and to identify the corresponding ligands, fractions of acid-extracted material from HLA-E/X63 transfectants were separated by reverse phase HPLC and were tested for their ability to enhance HLA-E cell surface expression [23].
  • Rejection of skin grafts from HLA-E transgenic mice demonstrates that HLA-E behaves as a transplantation Ag in mice [47].
  • Cell surface HLA-E was detected on lymph node cells by flow cytometry only in the presence of endogenous human beta2m [47].
  • Cell surface labeling of transfectants and immunoprecipitation with a monomorphic HLA class I-specific antibody or an antibody against human beta 2m confirmed the presence of an HLA-E H chain on the cell surface [48].
  • In particular, expression of HLA-E might favor tumor cell escape from CTL and NK immunosurveillance [4].


  1. The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells. Cohen, G.B., Gandhi, R.T., Davis, D.M., Mandelboim, O., Chen, B.K., Strominger, J.L., Baltimore, D. Immunity (1999) [Pubmed]
  2. Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Gumá, M., Angulo, A., Vilches, C., Gómez-Lozano, N., Malats, N., López-Botet, M. Blood (2004) [Pubmed]
  3. Low frequency of CD94/NKG2A+ T lymphocytes in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis, but not in asymptomatic carriers. Saito, M., Braud, V.M., Goon, P., Hanon, E., Taylor, G.P., Saito, A., Eiraku, N., Tanaka, Y., Usuku, K., Weber, J.N., Osame, M., Bangham, C.R. Blood (2003) [Pubmed]
  4. Expression and release of HLA-E by melanoma cells and melanocytes: potential impact on the response of cytotoxic effector cells. Derré, L., Corvaisier, M., Charreau, B., Moreau, A., Godefroy, E., Moreau-Aubry, A., Jotereau, F., Gervois, N. J. Immunol. (2006) [Pubmed]
  5. Thyrotropin-mediated repression of class II trans-activator expression in thyroid cells: involvement of STAT3 and suppressor of cytokine signaling. Kim, H., Suh, J.M., Hwang, E.S., Kim, D.W., Chung, H.K., Song, J.H., Hwang, J.H., Park, K.C., Ro, H.K., Jo, E.K., Chang, J.S., Lee, T.H., Lee, M.S., Kohn, L.D., Shong, M. J. Immunol. (2003) [Pubmed]
  6. MHC typing in variant Creutzfeldt-Jakob disease. Pepys, M.B., Bybee, A., Booth, D.R., Bishop, M.T., Will, R.G., Little, A.M., Prokupek, B., Madrigal, J.A. Lancet (2003) [Pubmed]
  7. Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy. Siebold, C., Hansen, B.E., Wyer, J.R., Harlos, K., Esnouf, R.E., Svejgaard, A., Bell, J.I., Strominger, J.L., Jones, E.Y., Fugger, L. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  8. Therapeutic efficacy of FcgammaRI/CD64-directed bispecific antibodies in B-cell lymphoma. Honeychurch, J., Tutt, A.L., Valerius, T., Heijnen, I.A., Van De Winkel, J.G., Glennie, M.J. Blood (2000) [Pubmed]
  9. Human CD4+ effector T cells mediate indirect interleukin-12- and interferon-gamma-dependent suppression of autologous HLA-negative lung tumor xenografts in severe combined immunodeficient mice. Egilmez, N.K., Hess, S.D., Chen, F.A., Takita, H., Conway, T.F., Bankert, R.B. Cancer Res. (2002) [Pubmed]
  10. Effector and Memory CTL Differentiation. Williams, M.A., Bevan, M.J. Annu. Rev. Immunol. (2007) [Pubmed]
  11. Cell biology of antigen processing in vitro and in vivo. Trombetta, E.S., Mellman, I. Annu. Rev. Immunol. (2005) [Pubmed]
  12. Antigen-specific memory B cell development. McHeyzer-Williams, L.J., McHeyzer-Williams, M.G. Annu. Rev. Immunol. (2005) [Pubmed]
  13. T lymphocyte-endothelial cell interactions. Choi, J., Enis, D.R., Koh, K.P., Shiao, S.L., Pober, J.S. Annu. Rev. Immunol. (2004) [Pubmed]
  14. Control of T cell viability. Marrack, P., Kappler, J. Annu. Rev. Immunol. (2004) [Pubmed]
  15. MHC supratypes as markers of null and defective C4 alleles in a Thai/Chinese population: relevance to disease susceptibility. Kay, P.H., Grimsley, G., Dawkins, R.L., Charoenwong, P. Dis. Markers (1987) [Pubmed]
  16. Rare variant of complement C4 is seen in high frequency in patients with primary glomerulonephritis. Wank, R., Schendel, D.J., O'Neill, G.J., Riethmüller, G., Held, E., Feucht, H.E. Lancet (1984) [Pubmed]
  17. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Mallal, S., Nolan, D., Witt, C., Masel, G., Martin, A.M., Moore, C., Sayer, D., Castley, A., Mamotte, C., Maxwell, D., James, I., Christiansen, F.T. Lancet (2002) [Pubmed]
  18. Tumor gene therapy made easy: allogeneic major histocompatibility complex in the C6 rat glioma model. Beutler, A.S., Banck, M.S., Wedekind, D., Hedrich, H.J. Hum. Gene Ther. (1999) [Pubmed]
  19. Crystal structure of an activation intermediate of cathepsin E. Ostermann, N., Gerhartz, B., Worpenberg, S., Trappe, J., Eder, J. J. Mol. Biol. (2004) [Pubmed]
  20. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Braud, V.M., Allan, D.S., O'Callaghan, C.A., Söderström, K., D'Andrea, A., Ogg, G.S., Lazetic, S., Young, N.T., Bell, J.I., Phillips, J.H., Lanier, L.L., McMichael, A.J. Nature (1998) [Pubmed]
  21. 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]
  22. Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Tomasec, P., Braud, V.M., Rickards, C., Powell, M.B., McSharry, B.P., Gadola, S., Cerundolo, V., Borysiewicz, L.K., McMichael, A.J., Wilkinson, G.W. Science (2000) [Pubmed]
  23. Impaired intracellular transport and cell surface expression of nonpolymorphic HLA-E: evidence for inefficient peptide binding. Ulbrecht, M., Kellermann, J., Johnson, J.P., Weiss, E.H. J. Exp. Med. (1992) [Pubmed]
  24. 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]
  25. Selective expansion of intraepithelial lymphocytes expressing the HLA-E-specific natural killer receptor CD94 in celiac disease. Jabri, B., de Serre, N.P., Cellier, C., Evans, K., Gache, C., Carvalho, C., Mougenot, J.F., Allez, M., Jian, R., Desreumaux, P., Colombel, J.F., Matuchansky, C., Cugnenc, H., Lopez-Botet, M., Vivier, E., Moretta, A., Roberts, A.I., Ebert, E.C., Guy-Grand, D., Brousse, N., Schmitz, J., Cerf-Bensussan, N. Gastroenterology (2000) [Pubmed]
  26. HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Lee, N., Llano, M., Carretero, M., Ishitani, A., Navarro, F., López-Botet, M., Geraghty, D.E. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  27. A GATA factor mediates cell type-restricted induction of HLA-E gene transcription by gamma interferon. Barrett, D.M., Gustafson, K.S., Wang, J., Wang, S.Z., Ginder, G.D. Mol. Cell. Biol. (2004) [Pubmed]
  28. The HLA-A2 restricted T cell epitope HCV core 35-44 stabilizes HLA-E expression and inhibits cytolysis mediated by natural killer cells. Nattermann, J., Nischalke, H.D., Hofmeister, V., Ahlenstiel, G., Zimmermann, H., Leifeld, L., Weiss, E.H., Sauerbruch, T., Spengler, U. Am. J. Pathol. (2005) [Pubmed]
  29. HLA-E surface expression depends on binding of TAP-dependent peptides derived from certain HLA class I signal sequences. Lee, N., Goodlett, D.R., Ishitani, A., Marquardt, H., Geraghty, D.E. J. Immunol. (1998) [Pubmed]
  30. Polymorphism at the HLA-E locus predates most HLA-A and -B polymorphism. Geraghty, D.E., Stockschleader, M., Ishitani, A., Hansen, J.A. Hum. Immunol. (1992) [Pubmed]
  31. HLA-E is the only class I gene that escapes CpG methylation and is transcriptionally active in the trophoblast-derived human cell line JAR. Boucraut, J., Guillaudeux, T., Alizadeh, M., Boretto, J., Chimini, G., Malecaze, F., Semana, G., Fauchet, R., Pontarotti, P., Le Bouteiller, P. Immunogenetics (1993) [Pubmed]
  32. Extended MHC haplotypes and CYP21/C4 gene organisation in Irish 21-hydroxylase deficiency families. Sinnott, P.J., Costigan, C., Dyer, P.A., Harris, R., Strachan, T. Hum. Genet. (1991) [Pubmed]
  33. A signal peptide derived from hsp60 binds HLA-E and interferes with CD94/NKG2A recognition. Michaëlsson, J., Teixeira de Matos, C., Achour, A., Lanier, L.L., Kärre, K., Söderström, K. J. Exp. Med. (2002) [Pubmed]
  34. Requirement of the proteasome for the trimming of signal peptide-derived epitopes presented by the nonclassical major histocompatibility complex class I molecule HLA-E. Bland, F.A., Lemberg, M.K., McMichael, A.J., Martoglio, B., Braud, V.M. J. Biol. Chem. (2003) [Pubmed]
  35. HLA-E is expressed on trophoblast and interacts with CD94/NKG2 receptors on decidual NK cells. King, A., Allan, D.S., Bowen, M., Powis, S.J., Joseph, S., Verma, S., Hiby, S.E., McMichael, A.J., Loke, Y.W., Braud, V.M. Eur. J. Immunol. (2000) [Pubmed]
  36. Production, crystallization, and preliminary X-ray analysis of the human MHC class Ib molecule HLA-E. O'Callaghan, C.A., Tormo, J., Willcox, B.E., Blundell, C.D., Jakobsen, B.K., Stuart, D.I., McMichael, A.J., Bell, J.I., Jones, E.Y. Protein Sci. (1998) [Pubmed]
  37. The human CD94 gene encodes multiple, expressible transcripts including a new partner of NKG2A/B. Lieto, L.D., Maasho, K., West, D., Borrego, F., Coligan, J.E. Genes Immun. (2006) [Pubmed]
  38. 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]
  39. Mitogen-activated protein kinase activity is involved in effector functions triggered by the CD94/NKG2-C NK receptor specific for HLA-E. Carretero, M., Llano, M., Navarro, F., Bellón, T., López-Botet, M. Eur. J. Immunol. (2000) [Pubmed]
  40. Analysis of HLA-E expression in human tumors. Marín, R., Ruiz-Cabello, F., Pedrinaci, S., Méndez, R., Jiménez, P., Geraghty, D.E., Garrido, F. Immunogenetics (2003) [Pubmed]
  41. Th1- and Th2-like cytokine production by first trimester decidual large granular lymphocytes is influenced by HLA-G and HLA-E. Rieger, L., Hofmeister, V., Probe, C., Dietl, J., Weiss, E.H., Steck, T., Kämmerer, U. Mol. Hum. Reprod. (2002) [Pubmed]
  42. 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]
  43. Chromosomal organization of the human major histocompatibility complex class I gene family. Koller, B.H., Geraghty, D.E., DeMars, R., Duvick, L., Rich, S.S., Orr, H.T. J. Exp. Med. (1989) [Pubmed]
  44. 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]
  45. HLA-G and HLA-E: fundamental and pathophysiological aspects. Carosella, E.D., Paul, P., Moreau, P., Rouas-Freiss, N. Immunol. Today (2000) [Pubmed]
  46. Kinetics and peptide dependency of the binding of the inhibitory NK receptor CD94/NKG2-A and the activating receptor CD94/NKG2-C to HLA-E. Valés-Gómez, M., Reyburn, H.T., Erskine, R.A., López-Botet, M., Strominger, J.L. EMBO J. (1999) [Pubmed]
  47. Cell-surface expression and alloantigenic function of a human nonclassical class I molecule (HLA-E) in transgenic mice. Pacasova, R., Martinozzi, S., Boulouis, H.J., Ulbrecht, M., Vieville, J.C., Sigaux, F., Weiss, E.H., Pla, M. J. Immunol. (1999) [Pubmed]
  48. The HLA-E gene encodes two differentially regulated transcripts and a cell surface protein. Ulbrecht, M., Honka, T., Person, S., Johnson, J.P., Weiss, E.H. J. Immunol. (1992) [Pubmed]
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