REVIEW Antonio Arnaiz-Villena Jorge Martinez-Laso Miguel Alvarez Maria J. Castro Pilar Varela Eduardo Gomez-Casado Belen Suarez Marı ´a Jose ´ Recio Gilberto Vargas-Alarco ´n Pablo Morales Received: 28 January 1997 / Revised: 17 March 1997 Sequences used in this compilation (Figs. 1, 2) are from: Alvarez et al. 1997; Boyson et al. 1995; Castro et al. 1996, and unpublished; Corell et al. 1994; Geraghty et al. 1987, 1992; Gomez-Casado et al. 1997; Koller et al. 1988; Morales et al. 1993; Ohya et al. 1990; Pook et al. 1991; Suarez et al. 1997, and unpublished; Summers et al. 1993; Watkins et al. 1993; Yamashita et al. 1996. The ape nomenclature equivalents are: Chimpanzee (Pan troglody- tes=Patr, Pan paniscus=Papa), Gorilla (Gorilla gorilla=- Gogo), Orangutan (Pongo pygmaeus=Popy), Rhesus mon- key (Macaca mulatta=Mamu), Cynomolgous monkey (Ma- caca fascicularis=Mafa), and Green monkey (Cercopitecus aethiops=Ceae). HLA-G*01011 and G*0102 present varia- tions only in the untranslated regions. Chimpanzee, Oran- gutan, Gorilla, Rhesus monkey, Cynomolgous monkey, and Green monkey Mhc-G alleles have been renamed as fol- lows: Patr-G*01 (Patr-G*I), Patr-G*02 (Patr-G*II), Papa- G*01 (Papa-G*I), Gogo-G*01 (Gogo-G*01), Popy-G*01 (Popy-G*I), Popy-G*02 (Popy-G*II), Popy-G*03 (Popy- G*III), Popy-G*04 (Popy-G*IV), Popy-G*05 (Popy-G*V), Mamu-G*01 (Mamu-G*I), Mamu-G*02 (Mamu-G*II), Mamu-G*03 (Mamu-G*III), Mamu-G*04 (Mamu-G*IV), Mamu-G*05 (Mamu-G*V), Mamu-G*06 (Mamu-G*VI), Mamu-G*07 (Mamu-G*VII), Mafa-G*01 (Mafa-G*I), Mafa-G*02 (Mafa-G*II), Mafa-G*03 (Mafa-G*III), Mafa- G*04 (Mafa-G*IV), Mafa-G*05 (Mafa-G*V), Mafa-G*06 (Mafa-G*VI), Mafa-G*07 (Mafa-G*VII), Ceae-G*01 (Ceae-G*I), Ceae-G*02 (Ceae-G*II), and Ceae-G*03 (Ceae-G*III). Accession codes for these sequences are shown in Table 1. Mamu-E*0101 and Mafa-E*04 exon 2 and exon 3 sequences are identical to each other. This is the first example of identity at the peptide binding site (PBS) in major histocompatibility complex (MHC) class I molecules belonging to two different species; Patr-E*02 and Papa- E*01, were also found to be identical (Figs. 1, 2). HLA-G molecules show very little productive polymor- phism and do not affect either the T-cell receptor or the peptide binding site (see Fig. 3). It is possible that these molecules do not present antigens, because all individuals from the Cercopithecinae family (Rhesus, Green, and Cynomolgous monkies) lack the α2 domain of the protein (Castro et al. 1996). All HLA-G isoforms described so far contain the α1 domain, which may suffice for accomplish- ing the function of the molecule (Ishitani and Geraghty 1992; Carosella et al. 1996). Cytotrophoblast expresses all the isoforms of MHC-G, including the soluble ones; no other MHC class I or class II antigen is expressed (except for transient low density HLA-C molecules) in this tissue (Wei and Orr 1990; Chumbley et al. 1993; King et al. 1996). It is possible that soluble or membrane-bound MHC- G molecules send negative signals to maternal NK cells through α1 domain determinants. HLA-E transcripts are found in many tissues; however, it is doubtful whether HLA-E molecules reach the surface of normal tissues (Ulbrecht et al. 1992a,b). The very few productive allelic changes found (see Fig. 3) only affect the T-cell receptor binding site (Bjorkman et al. 1987), suggesting that HLA-E function may be related to the T-cell repertoire shaping in the thymus or to presenting a rela- tively limited peptide repertoire. Both HLA-G and -E molecules do not show the three typical hypervariable regions at the peptide binding site, like classical class I HLA molecules, suggesting an alto- A. Arnaiz-Villena* ( ) J. Martinez-Laso* M. Alvarez M.J. Castro P. Varela E. Gomez-Casado B. Suarez M.J. Recio G. Vargas-Alarco ´n P. Morales Department of Immunology, Hospital 12 de Octubre, Universidad Complutense, Carretera Andalucia, E-28041 Madrid, Spain * The contribution by Antonio Arnaiz-Villena and Jorge Martinez-Laso is equal and the order of authorship is arbitrary. Immunogenetics (1997) 46: 251 – 266 Springer-Verlag 1997
Transcript
REVIEW
Antonio Arnaiz-Villena ? Jorge Martinez-LasoMiguel Alvarez ? Maria J. Castro ? Pilar VarelaEduardo Gomez-Casado? Belen SuarezMarı a JoseRecio ? Gilberto Vargas-AlarconPablo Morales
Primate Mhc-E and -G alleles
Received: 28 January 1997 / Revised: 17 March 1997
Structure
Sequences used in this compilation (Figs. 1, 2) are from:Alvarez et al. 1997; Boyson et al. 1995; Castro et al. 1996,and unpublished; Corell et al. 1994; Geraghty et al. 1987,1992; Gomez-Casado et al. 1997; Koller et al. 1988;Morales et al. 1993; Ohya et al. 1990; Pook et al. 1991;Suarez et al. 1997, and unpublished; Summers et al. 1993;Watkins et al. 1993; Yamashita et al. 1996. The apenomenclature equivalents are: Chimpanzee (Pan troglody-tes=Patr, Pan paniscus=Papa), Gorilla (Gorilla gorilla=-Gogo), Orangutan (Pongo pygmaeus=Popy), Rhesus mon-key (Macaca mulatta=Mamu), Cynomolgous monkey (Ma-caca fascicularis=Mafa), and Green monkey (Cercopitecusaethiops=Ceae). HLA-G*01011andG*0102present varia-tions only in the untranslated regions. Chimpanzee, Oran-gutan, Gorilla, Rhesus monkey, Cynomolgous monkey, andGreen monkeyMhc-G alleles have been renamed as fol-lows: Patr-G*01 (Patr-G*I), Patr-G*02 (Patr-G*II ), Papa-G*01 (Papa-G*I), Gogo-G*01 (Gogo-G*01), Popy-G*01(Popy-G*I), Popy-G*02 (Popy-G*II), Popy-G*03 (Popy-G*III ), Popy-G*04(Popy-G*IV), Popy-G*05(Popy-G*V),Mamu-G*01 (Mamu-G*I), Mamu-G*02 (Mamu-G*II),Mamu-G*03 (Mamu-G*III), Mamu-G*04 (Mamu-G*IV),Mamu-G*05 (Mamu-G*V), Mamu-G*06 (Mamu-G*VI),Mamu-G*07 (Mamu-G*VII), Mafa-G*01 (Mafa-G*I),Mafa-G*02 (Mafa-G*II), Mafa-G*03 (Mafa-G*III ), Mafa-G*04 (Mafa-G*IV), Mafa-G*05 (Mafa-G*V), Mafa-G*06(Mafa-G*VI), Mafa-G*07 (Mafa-G*VII), Ceae-G*01
(Ceae-G*I), Ceae-G*02 (Ceae-G*II), and Ceae-G*03(Ceae-G*III). Accession codes for these sequences areshown in Table 1.Mamu-E*0101and Mafa-E*04 exon 2and exon 3 sequences are identical to each other. This is thefirst example of identity at the peptide binding site (PBS) inmajor histocompatibility complex (MHC) class I moleculesbelonging to two different species;Patr-E*02 and Papa-E*01, were also found to be identical (Figs. 1, 2).
Function
HLA-G molecules show very little productive polymor-phism and do not affect either the T-cell receptor or thepeptide binding site (see Fig. 3). It is possible that thesemolecules do not present antigens, because all individualsfrom the Cercopithecinaefamily (Rhesus, Green, andCynomolgous monkies) lack theα2 domain of the protein(Castro et al. 1996). All HLA-G isoforms described so farcontain theα1 domain, which may suffice for accomplish-ing the function of the molecule (Ishitani and Geraghty1992; Carosella et al. 1996). Cytotrophoblast expresses allthe isoforms of MHC-G, including the soluble ones; noother MHC class I or class II antigen is expressed (exceptfor transient low density HLA-C molecules) in this tissue(Wei and Orr 1990; Chumbley et al. 1993; King et al.1996). It is possible that soluble or membrane-bound MHC-G molecules send negative signals to maternal NK cellsthroughα1 domain determinants.
HLA-E transcripts are found in many tissues; however, itis doubtful whether HLA-E molecules reach the surface ofnormal tissues (Ulbrecht et al. 1992a,b). The very fewproductive allelic changes found (see Fig. 3) only affectthe T-cell receptor binding site (Bjorkman et al. 1987),suggesting that HLA-E function may be related to the T-cellrepertoire shaping in the thymus or to presenting a rela-tively limited peptide repertoire.
Both HLA-G and -E molecules do not show the threetypical hypervariable regions at the peptide binding site,like classical class I HLA molecules, suggesting an alto-
A. Arnaiz-Villena* ( ) ? J. Martinez-Laso*? M. AlvarezM.J. Castro? P. Varela? E. Gomez-Casado? B. Suarez? M.J. RecioG. Vargas-Alarco´n ? P. MoralesDepartment of Immunology, Hospital 12 de Octubre, UniversidadComplutense, Carretera Andalucia, E-28041 Madrid, Spain
* The contribution by Antonio Arnaiz-Villena and Jorge Martinez-Lasois equal and the order of authorship is arbitrary.
gether different functionality and different evolutive con-straints; -E and -G molecules may use peptides only toreach the cell surface and may send negative signals to NKand T lymphocytes (tolerance).
The cell BeWo was thought to be homozygous for HLA-G*01012; however, it was later found to be heterozygous(G*01012, G*01013) and the G*01012 DNA sequence wasalso found to be wrong: codon 105 should be TCC and notTCG (Castro et al. 1996).
Intron 2 sequences of the allelesHLA-G*01011,G*01012, G*01013, G*0104,and G*0105N were se-quenced by us in the present work.
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Table 1mAccession codes for theMhc-E and -G sequences
* Popy-G*05was also sequenced by us in the present work
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Fig. 1 (For legend see page 261)
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Fig. 1 (Continued; for legend see page 261)
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Fig. 1 (Continued; for legend see page 261)
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Fig. 1 (Continued; for legend see page 261)
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Fig. 1 (Continued; for legend see page 261)
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Fig. 1 (Continued; for legend see page 261)
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Fig. 1 (Continued; for legend see page 261)
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Fig. 1 (Continued; for legend see page 261)
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Fig. 1mExon 1, 2, 3, 4, 5, 6, 7, and 8 sequences of theMhc-Eand-G in primates. Identity between residues is indicated by adash(-) and deletionsare denoted by anasterisk(*). Exon 7 of HLA-G*01012 is not shown because it is not comprised in the cDNA sequence available. Exonicconsensus class I sequence is from Watkins and co-workers (1993)
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Fig. 2 (For legend see page 265)
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Fig. 2 (Continued; for legend see page 265)
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Fig. 2 (Continued; for legend see page 265)
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Fig. 2mIntron 1, 2, 3, 4, 5, 6, and 7 sequences of theMhc-E and-G alleles in primates. Identity between residues is indicated by adash(-) anddeletions are denoted by anasterisk(*). Intronic consensus class I sequence is from Summers and co-workers (1993), slightly modified, accordingto our findings inHLA-E and -G DNA sequences
AcknowledgmentsmThis work was supported by Fondo de In-vestigaciones Sanitarias, Ministerio de Sanidad, PM-95/97 (Ministeriode Educacio´n), and Fundacio´n Ramon Areces, Spain. We are gratefulto J.M. Martin-Villa for his collaboration.
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Note added in proof: Two new partial cDNA sequences fromMamu-G have been published (Boysen et al. 1996) since this review went topress
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Fig. 3 Exon 1 and 2.mSeveral synonymous changes there exist inHLA-G and-E allelic DNA sequences; however, nonsynonymous changes inhumans are very restricted and they are indicated in the Figure. (*,changes forHLA-G alleles;*, changes forHLA-E alleles)
