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• W2070214550 abstract "Previous studies of HLA-E allelic polymorphism have indicated that balancing selection may be acting to maintain two major alleles in most populations, indicating that a functional difference may exist between the alleles. The alleles differ at only one amino acid position, where an arginine at position 107 in HLA-E*0101 (ER) is replaced by a glycine in HLA-E*0103 (EG). To investigate possible functional differences, we have undertaken a study of the physical and biochemical properties of these two proteins. By comparing expression levels, we found that whereas steady-state protein levels were similar, the two alleles did in fact differ with respect to cell surface levels. To help explain this difference, we undertook studies of the relative differences in peptide affinity, complex stability, and three-dimensional structure between the alleles. The crystal structures for HLA-EG complexed with two distinct peptides were determined, and both were compared with the HLA-ERstructure. No significant differences in the structure of HLA-E were induced as a result of binding different peptides or by the allelic substitution at position 107. However, there were clear differences in the relative affinity for peptide of each heavy chain, which correlated with and may be explained by differences between their thermal stabilities. These differences were completely consistent with the relative levels of the HLA-E alleles on the cell surface and may indeed correlate with functional differences. This in turn may help explain the apparent balancing selection acting on this locus. Previous studies of HLA-E allelic polymorphism have indicated that balancing selection may be acting to maintain two major alleles in most populations, indicating that a functional difference may exist between the alleles. The alleles differ at only one amino acid position, where an arginine at position 107 in HLA-E*0101 (ER) is replaced by a glycine in HLA-E*0103 (EG). To investigate possible functional differences, we have undertaken a study of the physical and biochemical properties of these two proteins. By comparing expression levels, we found that whereas steady-state protein levels were similar, the two alleles did in fact differ with respect to cell surface levels. To help explain this difference, we undertook studies of the relative differences in peptide affinity, complex stability, and three-dimensional structure between the alleles. The crystal structures for HLA-EG complexed with two distinct peptides were determined, and both were compared with the HLA-ERstructure. No significant differences in the structure of HLA-E were induced as a result of binding different peptides or by the allelic substitution at position 107. However, there were clear differences in the relative affinity for peptide of each heavy chain, which correlated with and may be explained by differences between their thermal stabilities. These differences were completely consistent with the relative levels of the HLA-E alleles on the cell surface and may indeed correlate with functional differences. This in turn may help explain the apparent balancing selection acting on this locus. The major histocompatibility complex (MHC) 1The abbreviations used are: MHC, major histocompatibility complex; β2m, β2-microglobulin; MES, 4-morpholineethanesulfonic acid; Pipes, 1,4-piperazinediethanesulfonic acid; NK, natural killer; FACS, fluorescence-activated cell sorting; LCL, lymphoblastoid cell line 1The abbreviations used are: MHC, major histocompatibility complex; β2m, β2-microglobulin; MES, 4-morpholineethanesulfonic acid; Pipes, 1,4-piperazinediethanesulfonic acid; NK, natural killer; FACS, fluorescence-activated cell sorting; LCL, lymphoblastoid cell line in humans includes the HLA loci, a group of genes encoding glycoproteins that control cell-to-cell interactions and regulate immune responses. These include the classical class I loci HLA-A, -B, and -C, whose role in immunological recognition is now well understood (1Townsend A. Bodmer H. Ann. Rev. Immunol. 1989; 7: 601-624Crossref PubMed Scopus (1105) Google Scholar). In addition to these genes, the MHC contains three highly homologous, nonclassical class I genes, HLA-E, -F, and -G, each of which probably plays a specialized role in the immune response. All three genes are located in relatively close proximity within the class I region and together with the classical class I antigens constitute the complete list of active class I genes in humans (2Geraghty D.E. Koller B.H. Hansen J.A. Orr H.T. J. Immunol. 1992; 149: 1934-1946PubMed Google Scholar). The remainder of the class I-like sequences are apparently pseudogenes (e.g. HLA-H), gene fragments, and other inactive but structurally homologous sequences. Each of the nonclassical class I genes can be distinguished from classical class I genes by their expression levels, as is the case for HLA-E, which is ubiquitously expressed but at much lower relative levels (3Lee N. Llano M. Carretero M. Ishitani A. Navarro F. Lopez-Botet M. Geraghty D.E. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5199-5204Crossref PubMed Scopus (809) Google Scholar), or by their tissue-specific expression patterns in the case of HLA-G (4Kovats S. Main E.K. Librach C. Stubblebine M. Fisher S.J. DeMars R. Science. 1990; 248: 220-223Crossref PubMed Scopus (1214) Google Scholar) and HLA-F (5Geraghty D.E. Wei X.H. Orr H.T. Koller B.H. J. Exp. Med. 1990; 171: 1-18Crossref PubMed Scopus (177) Google Scholar, 6Lepin E.J. Bastin J.M. Allan D.S. Roncador G. Braud V.M. Mason D.Y. van der Merwe P.A. McMichael A.J. Bell J.I. Powis S.H. O'Callaghan C.A. Eur. J. Immunol. 2000; 30: 3552-3561Crossref PubMed Scopus (166) Google Scholar). Each is hypothesized to have a unique function in immune responses.Of the three nonclassical class I genes, the function of HLA-E has been the most completely elucidated through its interaction with CD94-NKG2 receptors (3Lee N. Llano M. Carretero M. Ishitani A. Navarro F. Lopez-Botet M. Geraghty D.E. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5199-5204Crossref PubMed Scopus (809) Google Scholar, 7Braud V.M. Allan D.S. O'Callaghan C.A. Soderstrom 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; 391: 795-799Crossref PubMed Scopus (1715) Google Scholar). CD94 is a type II glycoprotein that is expressed on most NK cells and a subset of T lymphocytes (8Aramburu J. Balboa M.A. Izquierdo M. Lopez-Botet M. J. Immunol. 1991; 147: 714-721PubMed Google Scholar, 9Aramburu J. Balboa M.A. Ramirez A. Silva A. Acevedo A. Sanchez-Madrid F. De Landazuri M.O. Lopez-Botet M. J. Immunol. 1990; 144: 3238-3247PubMed Google Scholar). It forms a heterodimer with the NKG2A/B, NKG2C, NKG2E, and NKG2H glycoproteins (10Bellon T. Heredia A.B. Llano M. Minguela A. Rodriguez A. Lopez-Botet M. Aparicio P. J. Immunol. 1999; 162: 3996-4002PubMed Google Scholar, 11Lazetic S. Chang C. Houchins J.P. Lanier L.L. Phillips J.H. J. Immunol. 1996; 157: 4741-4745PubMed Google Scholar). Interaction with such CD94 heterodimers can augment, inhibit, or have no effect on NK cell-mediated cytotoxicity and cytokine production (12Perez-Villar J.J. Melero I. Rodriguez A. Carretero M. Aramburu J. Sivori S. Orengo A.M. Moretta A. Lopez-Botet M. J. Immunol. 1995; 154: 5779-5788PubMed Google Scholar). Surface expression of HLA-E requires, and is therefore controlled by, the availability of any of a set of highly conserved nonamer peptides that are available from the signal sequences of other HLA class I molecules including HLA-A, -B, -C, and -G but not HLA-F (13Lee N. Goodlett D.R. Ishitani A. Marquardt H. Geraghty D.E. J. Immunol. 1998; 160: 4951-4960PubMed Google Scholar). When peptide is available, the resultant complex can interact normally with the CD94-NKG2 complex (3Lee N. Llano M. Carretero M. Ishitani A. Navarro F. Lopez-Botet M. Geraghty D.E. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5199-5204Crossref PubMed Scopus (809) Google Scholar, 7Braud V.M. Allan D.S. O'Callaghan C.A. Soderstrom 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; 391: 795-799Crossref PubMed Scopus (1715) Google Scholar). Further, the ability of HLA-E complexes to interact with CD94-NKG2 ligands is affected by the particular nonamer that is available for binding. For example, HLA-E may gain a novel function when it binds the unique peptide that only HLA-G can provide (14Llano M. Lee N. Navarro F. Garcia P. Albar J.P. Geraghty D.E. Lopez-Botet M. Eur. J. Immunol. 1998; 28: 2854-2863Crossref PubMed Scopus (320) Google Scholar). Since HLA-E is also expressed in those placental cells normally expressing HLA-G, such a potentially activating function is suggestive of a unique role that HLA-E might be playing in the placenta.Polymorphism among HLA class I antigens has long been thought of as a hallmark of the functional diversity required of these molecules (15Little A.M. Parham P. Rev. Immunogenet. 1999; 1: 105-123PubMed Google Scholar). Whereas high levels of polymorphism in HLA class I have been maintained by overdominant selection (16Hughes A.L. Nei M. Nature. 1988; 335: 167-170Crossref PubMed Scopus (1475) Google Scholar), in contrast the nonclassical class I molecules HLA-E, -F, and -G have been under a distinct selective pressure, exhibiting very low levels of allelic polymorphism. Two nonsynonymous alleles of HLA-E have been found, E*0101 and E*0103 (17Geraghty D.E. Stockschleader M. Ishitani A. Hansen J.A. Hum. Immunol. 1992; 33: 174-184Crossref PubMed Scopus (102) Google Scholar,18Matte C. Lacaille J. Zijenah L. Ward B. Roger M. Hum. Immunol. 2000; 61: 1150-1156Crossref PubMed Scopus (80) Google Scholar), and although others have been reported, it appears likely that they are the result of sequencing artifacts (19Grimsley C. Kawasaki A. Gassner C. Sageshima N. Nose Y. Hatake K. Geraghty D.E. Ishitani A. Tissue Antigens. 2002; 60: 206-212Crossref PubMed Scopus (77) Google Scholar). The two confirmed HLA-E alleles have been referred to as HLA-EG (E*0101) and HLA-ER (E*0103), since they are distinguished by having either an arginine (-ER) or a glycine (-EG) at position 107 of the protein, located on a loop between β-strands in the α2 domain of the heavy chain. HLA-EG and -ER are found at nearly equal frequencies in diverse populations. Evidence that some form of balancing selection is acting on this gene to maintain the two alleles of HLA-E has been reported (20Grimsley C. Ober C. Hum. Immunol. 1997; 52: 33-40Crossref PubMed Scopus (111) Google Scholar). Such selection would imply that there are functional differences between the two alleles.In order to investigate the underlying rationale for potential functional differences, we examined the two HLA-E alleles individually for various characteristics that might affect function. Preliminary evidence had indicated that different levels of surface expression of HLA-E could alter its ability to protect cells from NK lysis by NKL cells (3Lee N. Llano M. Carretero M. Ishitani A. Navarro F. Lopez-Botet M. Geraghty D.E. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5199-5204Crossref PubMed Scopus (809) Google Scholar). 2N. Lee, unpublished results. 2N. Lee, unpublished results. Therefore, we examined the HLA-E alleles for differential surface expression levels and, having found evidence for this, undertook experiments to understand the physical basis for these differences. By comparing differences in peptide affinity, three-dimensional structure, and thermal stability of the HLA-EG and -ER in complex with various peptides, we were able to elucidate important differences in the physical characteristics of these molecules that may form the basis underlying the effective balancing selection that appears to have been acting on this locus.DISCUSSIONIn the present study, we opened a thorough investigation of the biochemical differences between the two nonsynonymous HLA-E alleles. This study was motivated primarily by our initial observation that, in most cases, the HLA-EG allele was expressed at higher levels than the HLA-ER allele in human transfected cells regardless of which peptide was bound. This observation was confirmed by a similar comparative analysis of HLA-E expression on normal cells, where, to a degree depending on the available classical class I signal sequences, the HLA-EG allele was expressed at significantly higher levels. Since studies have suggested that cell surface levels of HLA-E can affect the signaling through CD94-NKG2 (3Lee N. Llano M. Carretero M. Ishitani A. Navarro F. Lopez-Botet M. Geraghty D.E. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5199-5204Crossref PubMed Scopus (809) Google Scholar, 14Llano M. Lee N. Navarro F. Garcia P. Albar J.P. Geraghty D.E. Lopez-Botet M. Eur. J. Immunol. 1998; 28: 2854-2863Crossref PubMed Scopus (320) Google Scholar, 43Vales-Gomez M. Reyburn H.T. Erskine R.A. Lopez-Botet M. Strominger J.L. EMBO J. 1999; 18: 4250-4260Crossref PubMed Scopus (293) Google Scholar), such a physical difference in cell surface expression levels might be translated into functional differences between these molecules. An additional dimension of complexity is introduced by the identity of the bound peptide and the particular allele, since such functional differences have been demonstrated to depend on these factors for HLA-E (14Llano M. Lee N. Navarro F. Garcia P. Albar J.P. Geraghty D.E. Lopez-Botet M. Eur. J. Immunol. 1998; 28: 2854-2863Crossref PubMed Scopus (320) Google Scholar).We first considered the possibility that the substitution of glycine for arginine at position 107 would result in structural differences between the two alleles, and since the crystal structure of HLA-ER had been solved (38O'Callaghan C.A. Tormo J. Willcox B.E. Braud V.M. Jakobsen B.K. Stuart D.I. McMichael A.J. Bell J.I. Jones E.Y. Mol. Cell. 1998; 1: 531-541Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar), we undertook the crystallographic analysis of HLA-EG complexed with two different peptides. However, the structures of the peptide-binding, α1α2 platform domains of HLA-E with either peptide bound to either of the two alleles are essentially identical within the accuracy of the analysis. Therefore, the structures do not immediately provide an explanation for the significant difference in the stability of the two alleles. The one structural difference that is observed between HLA-EG and HLA-ER is the presence of an additional hydrogen bond in the HLA-ER molecule involving the side chain of arginine 107, although this might naively imply that the HLA-EG allele would be less stable than the HLA-ER allele, the opposite of what is observed. Likewise, the presence of an additional glycine in the HLA-E sequence would be predicted to result in a larger loss of entropy during folding, destabilizing the HLA-EG structure relative to HLA-ER, again the opposite of what is observed.Direct affects on stability, and thus indirect affects on cell-surface half-life and peptide or receptor affinity, can be explained by the gain or loss of stabilizing interactions between HLA-E alleles and the various bound peptides. Differences in the identity of the P2 residue of the peptide result in cavities within the peptide-platform domain complex structure by varying the quality of fit of the different peptides into an apparently rigid protein structure. The relative quality of the fit of peptide into platform correlates well with the differences in thermal stability and cell surface expression levels measured for HLA-E complexes with different peptides. As a consequence, each allele shows differing affinities with distinct peptides in a manner that correlates with the differing stability. The HLA-B27-derived nonamer provides a striking example of this difference. The HLA-EG heavy chain does form complexes with the B27 nonamer, albeit at relatively high concentrations, whereas the HLA-ER molecule does not bind the nonamer under the conditions tested. This is reflected precisely in surface expression using the hybrid constructs with the B27 signal sequence fused to either HLA-E allele, where no detectable HLA-ER was observed on the surface of 221 transfectants, whereas significant levels of surface HLA-EG were observed under the same conditions, and in T m measurements, where the stability of HLA-ER refolded in the presence of the B27 peptide is comparable with peptideless MHC class I proteins.The stability of the complexes was also consistent with a melting temperature of some 5 °C higher for the HLA-EG/B27 nonamer complex. Indeed, with all peptides tested, completely consistent differences were observed between the alleles among all three measures of cell surface expression level, peptide affinity, and complex stability. Thus, the differences in expression levels are not due exclusively to the affinities for available peptide or to any other single factor, but instead are due to the interrelated combination of relative affinity and stability of the refolded complex. The measurements of stability show clearly that the EG complex has a significantly higher melting temperature over ERregardless of the peptide bound. Further, it is unlikely that peptide is limiting, since classical class I molecules, the source of peptide, are over 20-fold more abundant than the HLA-E complex (13Lee N. Goodlett D.R. Ishitani A. Marquardt H. Geraghty D.E. J. Immunol. 1998; 160: 4951-4960PubMed Google Scholar). Further, previous peptide feeding experiments had indicated that steady state HLA-E levels were controlled by the half-life of the complex and not by limiting peptide (3Lee N. Llano M. Carretero M. Ishitani A. Navarro F. Lopez-Botet M. Geraghty D.E. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5199-5204Crossref PubMed Scopus (809) Google Scholar, 14Llano M. Lee N. Navarro F. Garcia P. Albar J.P. Geraghty D.E. Lopez-Botet M. Eur. J. Immunol. 1998; 28: 2854-2863Crossref PubMed Scopus (320) Google Scholar).Although these studies implicate differing surface levels of HLA-E as a possible modulator of ligand interaction, we have not ruled out an effect of the substitution at residue 107 as altering an interaction between HLA-E and CD94-NKG2. In experiments carried out with transfectants in vitro, essentially similar results were observed regardless of the HLA-E allele used (3Lee N. Llano M. Carretero M. Ishitani A. Navarro F. Lopez-Botet M. Geraghty D.E. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5199-5204Crossref PubMed Scopus (809) Google Scholar). Nevertheless, subtle effects that may have significance in vivo would probably not be detected in these experiments. However, no differences were observed in comparisons of HLA-EG and HLA-ERstructures that would directly or indirectly affect the interaction with NKG2-CD94 heterodimers. The possibility that TCRs recognize HLA-E directly (44Pietra G. Romagnani C. Falco M. Vitale M. Castriconi R. Pende D. Millo E. Anfossi S. Biassoni R. Moretta L. Mingari M.C. Eur. J. Immunol. 2001; 31: 3687-3693Crossref PubMed Scopus (81) Google Scholar) adds the possibility that this position affects interactions with receptors other than NKG2-CD94. Therefore, it is at least conceivable that the allelic variation has two effects on ligand interaction, one determining quantitative differences in the amount of HLA-E complexes on the cell surface at any given time and the second distinguishing the molecules qualitatively through alterations in the effective affinity for interacting receptors.The level of selection acting on the HLA-E locus to balance these alleles in the population is not entirely clear, although at least two possibilities can be envisioned. Whereas the present study was limited to an examination of HLA class I signal sequence-derived peptides, TCR-derived peptides have been reported to bind and be presented by HLA-E (45Li J. Goldstein I. Glickman-Nir E. Jiang H. Chess L. J. Immunol. 2001; 167: 3800-3808Crossref PubMed Scopus (73) Google Scholar). If, as these studies suggest, HLA-E does prove to be involved in TCR Vβ peptide presentation, the likelihood that these peptides show differential binding between the two alleles seems plausible. Indeed, of the seven peptides tested, in every case the relative affinity of peptide was higher for HLA-EG (Fig. 3). Evidence for pathogen-derived peptides binding and being presented by HLA-E has also been suggested (46Ulbrecht M. Modrow S. Srivastava R. Peterson P.A. Weiss E.H. J. Immunol. 1998; 160: 4375-4385PubMed Google Scholar), and evidence for recognition of HLA-E by TCR α/β seems to support such a possibility (44Pietra G. Romagnani C. Falco M. Vitale M. Castriconi R. Pende D. Millo E. Anfossi S. Biassoni R. Moretta L. Mingari M.C. Eur. J. Immunol. 2001; 31: 3687-3693Crossref PubMed Scopus (81) Google Scholar). It therefore is conceivable that selection for maintenance of two HLA-E alleles could be acting at the level of regulation of peripheral T cell function, of pathogen-mediated immune recognition, or both.Alternatively, an additional and significant level of balancing selection might operate via HLA-E expression in the placenta. Several facts go together to implicate this as a mechanism for a relatively rapid stabilization of a new allele in a population. First, placental trophoblasts expressing HLA-G also express HLA-E complexed with the HLA-G nonamer (47Ishitani A. Sageshima N. Lee N. Dorofeeva N. Hatake K.H.M. Geraghty D.E. J. Immunol. 2003; (in press)PubMed Google Scholar). A relatively large difference in binding affinity, derived from the differential ability of peptide to foster protein folding, between HLA-EG and HLA-ER for the HLA-G nonamer was observed (Fig. 3), suggesting a relative difference in surface expression levels between these alleles in the placenta. Since the HLA-E/G nonamer complex can evoke an inhibitory or stimulatory response from NK cells (14Llano M. Lee N. Navarro F. Garcia P. Albar J.P. Geraghty D.E. Lopez-Botet M. Eur. J. Immunol. 1998; 28: 2854-2863Crossref PubMed Scopus (320) Google Scholar) and since relative surface levels are likely to directly influence the efficiency of either inhibition or stimulation via CD94-NKG2, it is plausible that there is significant room for modulation of function in the arena of the maternal-placental immune interaction. Indeed, a unique NK response is associated with pregnancy (48King A. Burrows T. Verma S. Hiby S. Loke Y.W. Hum. Reprod. Update. 1998; 4: 480-485Crossref PubMed Scopus (178) Google Scholar), and rather than acting to inhibit NK activity in the maternal decidua, HLA-E may indeed act to stimulate NK to secrete cytokines appropriate for a stable immunological environment. The proper balance of inhibition and stimulation to yield a stable pregnancy may require higher or lower levels of HLA-E, depending upon other immunological and genetic factors present, thus conceivably providing strong selection on a newly introduced HLA-E allele. The major histocompatibility complex (MHC) 1The abbreviations used are: MHC, major histocompatibility complex; β2m, β2-microglobulin; MES, 4-morpholineethanesulfonic acid; Pipes, 1,4-piperazinediethanesulfonic acid; NK, natural killer; FACS, fluorescence-activated cell sorting; LCL, lymphoblastoid cell line 1The abbreviations used are: MHC, major histocompatibility complex; β2m, β2-microglobulin; MES, 4-morpholineethanesulfonic acid; Pipes, 1,4-piperazinediethanesulfonic acid; NK, natural killer; FACS, fluorescence-activated cell sorting; LCL, lymphoblastoid cell line in humans includes the HLA loci, a group of genes encoding glycoproteins that control cell-to-cell interactions and regulate immune responses. These include the classical class I loci HLA-A, -B, and -C, whose role in immunological recognition is now well understood (1Townsend A. Bodmer H. Ann. Rev. Immunol. 1989; 7: 601-624Crossref PubMed Scopus (1105) Google Scholar). In addition to these genes, the MHC contains three highly homologous, nonclassical class I genes, HLA-E, -F, and -G, each of which probably plays a specialized role in the immune response. All three genes are located in relatively close proximity within the class I region and together with the classical class I antigens constitute the complete list of active class I genes in humans (2Geraghty D.E. Koller B.H. Hansen J.A. Orr H.T. J. Immunol. 1992; 149: 1934-1946PubMed Google Scholar). The remainder of the class I-like sequences are apparently pseudogenes (e.g. HLA-H), gene fragments, and other inactive but structurally homologous sequences. Each of the nonclassical class I genes can be distinguished from classical class I genes by their expression levels, as is the case for HLA-E, which is ubiquitously expressed but at much lower relative levels (3Lee N. Llano M. Carretero M. Ishitani A. Navarro F. Lopez-Botet M. Geraghty D.E. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5199-5204Crossref PubMed Scopus (809) Google Scholar), or by their tissue-specific expression patterns in the case of HLA-G (4Kovats S. Main E.K. Librach C. Stubblebine M. Fisher S.J. DeMars R. Science. 1990; 248: 220-223Crossref PubMed Scopus (1214) Google Scholar) and HLA-F (5Geraghty D.E. Wei X.H. Orr H.T. Koller B.H. J. Exp. Med. 1990; 171: 1-18Crossref PubMed Scopus (177) Google Scholar, 6Lepin E.J. Bastin J.M. Allan D.S. Roncador G. Braud V.M. Mason D.Y. van der Merwe P.A. McMichael A.J. Bell J.I. Powis S.H. O'Callaghan C.A. Eur. J. Immunol. 2000; 30: 3552-3561Crossref PubMed Scopus (166) Google Scholar). Each is hypothesized to have a unique function in immune responses. Of the three nonclassical class I genes, the function of HLA-E has been the most completely elucidated through its interaction with CD94-NKG2 receptors (3Lee N. Llano M. Carretero M. Ishitani A. Navarro F. Lopez-Botet M. Geraghty D.E. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5199-5204Crossref PubMed Scopus (809) Google Scholar, 7Braud V.M. Allan D.S. O'Callaghan C.A. Soderstrom 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; 391: 795-799Crossref PubMed Scopus (1715) Google Scholar). CD94 is a type II glycoprotein that is expressed on most NK cells and a subset of T lymphocytes (8Aramburu J. Balboa M.A. Izquierdo M. Lopez-Botet M. J. Immunol. 1991; 147: 714-721PubMed Google Scholar, 9Aramburu J. Balboa M.A. Ramirez A. Silva A. Acevedo A. Sanchez-Madrid F. De Landazuri M.O. Lopez-Botet M. J. Immunol. 1990; 144: 3238-3247PubMed Google Scholar). It forms a heterodimer with the NKG2A/B, NKG2C, NKG2E, and NKG2H glycoproteins (10Bellon T. Heredia A.B. Llano M. Minguela A. Rodriguez A. Lopez-Botet M. Aparicio P. J. Immunol. 1999; 162: 3996-4002PubMed Google Scholar, 11Lazetic S. Chang C. Houchins J.P. Lanier L.L. Phillips J.H. J. Immunol. 1996; 157: 4741-4745PubMed Google Scholar). Interaction with such CD94 heterodimers can augment, inhibit, or have no effect on NK cell-mediated cytotoxicity and cytokine production (12Perez-Villar J.J. Melero I. Rodriguez A. Carretero M. Aramburu J. Sivori S. Orengo A.M. Moretta A. Lopez-Botet M. J. Immunol. 1995; 154: 5779-5788PubMed Google Scholar). Surface expression of HLA-E requires, and is therefore controlled by, the availability of any of a set of highly conserved nonamer peptides that are available from the signal sequences of other HLA class I molecules including HLA-A, -B, -C, and -G but not HLA-F (13Lee N. Goodlett D.R. Ishitani A. Marquardt H. Geraghty D.E. J. Immunol. 1998; 160: 4951-4960PubMed Google Scholar). When peptide is available, the resultant complex can interact normally with the CD94-NKG2 complex (3Lee N. Llano M. Carretero M. Ishitani A. Navarro F. Lopez-Botet M. Geraghty D.E. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5199-5204Crossref PubMed Scopus (809) Google Scholar, 7Braud V.M. Allan D.S. O'Callaghan C.A. Soderstrom 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; 391: 795-799Crossref PubMed Scopus (1715) Google Scholar). Further, the ability of HLA-E complexes to interact with CD94-NKG2 ligands is affected by the particular nonamer that is available for binding. For example, HLA-E may gain a novel function when it binds the unique peptide that only HLA-G can provide (14Llano M. Lee N. Navarro F. Garcia P. Albar J.P. Geraghty D.E. Lopez-Botet M. Eur. J. Immunol. 1998; 28: 2854-2863Crossref PubMed Scopus (320) Google Scholar). Since HLA-E is also expressed in those placental cells normally expressing HLA-G, such a potentially activating function is suggestive of a unique role that HLA-E might be playing in the placenta. Polymorphism among HLA class I antigens has long been thought of as a hallmark of the functional diversity required of these molecules (15Little A.M. Parham P. Rev. Immunogenet. 1999; 1: 105-123PubMed Google Scholar). Whereas high levels of polymorphism in HLA class I have been maintained by overdominant selection (16Hughes A.L. Nei M. Nature. 1988; 335: 167-170Crossref PubMed Scopus (1475) Google Scholar), in contrast the nonclassical class I molecules HLA-E, -F, and -G have been under a distinct selective pressure, exhibiting very low levels of allelic polymorphism. Two nonsynonymous alleles of HLA-E have been found, E*0101 and E*0103 (17Geraghty D.E. Stockschleader M. Ishitani A. Hansen J.A. Hum. Immunol. 1992; 33: 174-184Crossref PubMed Scopus (102) Google Scholar,18Matte C. Lacaille J. Zijenah L. Ward B. Roger M. Hum. Immunol. 2000; 61: 1150-1156Crossref PubMed Scopus (80) Google Scholar), and although others have been reported, it appears likely that they are the result of sequencing artifacts (19Grimsley C. Kawasaki A. Gassner C. Sageshima N. Nose Y. Hatake K. Geraghty D.E. Ishitani A. Tissue Antigens. 2002; 60: 206-212Crossref PubMed Scopus (77) Google Scholar). The two confirmed HLA-E alleles have been referred to as HLA-EG (E*0101) and HLA-ER (E*0103), since they are distingui" @default.
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