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Characterisation of RT1-E2, a multigenic family of highly conserved rat non-classical MHC class I molecules initially identified in cells from immunoprivileged sites.

Lau P, Amadou C, Brun H, Rouillon V, McLaren F, Le Rolle AF, Graham M, Butcher GW, Joly E - BMC Immunol. (2003)

Bottom Line: The RT1n MHC haplotype (found in BN rats) carries a single RT1-E2 locus, which lies in the RT1-C/E region of the MHC and displays the typical exon-intron organisation and promoter features seen in other rat MHC class I genes.Compared to other class I molecules, this suggests that RT1-E2 molecules may associate with well defined sets of ligands.Several characteristics point to a certain similarity to the mouse H2-Qa2 and human HLA-G molecules.

View Article: PubMed Central - HTML - PubMed

Affiliation: IFR Claude de Préval, INSERM U563, CHU Purpan, 31300 Toulouse, France. laupoui@pasteur.fr

ABSTRACT

Background: So-called "immunoprivileged sites" are tissues or organs where slow allograft rejection correlates with low levels of expression of MHC class I molecules. Whilst classical class I molecules are recognised by cytotoxic T lymphocytes (CTL), some MHC class I molecules are called "non-classical" because they exhibit low polymorphism and are not widely expressed. These last years, several studies have shown that these can play different, more specialised roles than their classical counterparts. In the course of efforts to characterise MHC class I expression in rat cells obtained from immunoprivileged sites such as the central nervous system or the placenta, a new family of non-classical MHC class I molecules, which we have named RT1-E2, has been uncovered.

Results: Members of the RT1-E2 family are all highly homologous to one another, and the number of RT1-E2 loci varies from one to four per MHC haplotype among the six rat strains studied so far, with some loci predicted to give rise to soluble molecules. The RT1n MHC haplotype (found in BN rats) carries a single RT1-E2 locus, which lies in the RT1-C/E region of the MHC and displays the typical exon-intron organisation and promoter features seen in other rat MHC class I genes. We present evidence that: i) RT1-E2 molecules can be detected at the surface of transfected mouse L cells and simian COS-7 cells, albeit at low levels; ii) their transport to the cell surface is dependent on a functional TAP transporter. In L cells, their transport is also hindered by protease inhibitors, brefeldin A and monensin.

Conclusions: These findings suggest that RT1-E2 molecules probably associate with ligands of peptidic nature. The high homology between the RT1-E2 molecules isolated from divergent rat MHC haplotypes is particularly striking at the level of their extra-cellular portions. Compared to other class I molecules, this suggests that RT1-E2 molecules may associate with well defined sets of ligands. Several characteristics point to a certain similarity to the mouse H2-Qa2 and human HLA-G molecules.

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Molecular modelling of RT1-E2u was carried out on the Swiss model server . The coordinates of 1ED3, 1QLF, 1HOC and 1CE6 were used by the server as templates to generate this model. The software Swiss PDB viewer was used to compare the resulting structure with those of RT1-Aa (1ED3), H2-Ld (1LDP) and H2-Qa2 (1K8D). Acidic residues are represented in red, basic in blue, and hydrophobic in yellow.
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Figure 9: Molecular modelling of RT1-E2u was carried out on the Swiss model server . The coordinates of 1ED3, 1QLF, 1HOC and 1CE6 were used by the server as templates to generate this model. The software Swiss PDB viewer was used to compare the resulting structure with those of RT1-Aa (1ED3), H2-Ld (1LDP) and H2-Qa2 (1K8D). Acidic residues are represented in red, basic in blue, and hydrophobic in yellow.

Mentions: The Qa2 molecules have been shown to associate with peptide ligands [58] and to depend on the TAP transporter for their expression at the cell surface [59]. The recent crystallographic resolution of the Qa2 molecule derived from the Q9 locus in combination with a nonameric self peptide revealed a shallow hydrophobic groove, providing a plausible explanation for the relatively promiscuous specificity of this MHC class Ib molecule for peptides [60]. When we used molecular modelling to visualise the peptide binding groove of RT1-E2 molecules, we were struck by the overall similarity of the peptide binding groove with that of H2-Qa2 (Figure 9). Not only do both molecules harbour a very hydrophobic F pocket, but they also carry histidine residues at position 9 and 70, which could, as in H2-Qa2, result in the absence of a C pocket, and in the bulging of peptides out of the middle of the peptide binding groove.


Characterisation of RT1-E2, a multigenic family of highly conserved rat non-classical MHC class I molecules initially identified in cells from immunoprivileged sites.

Lau P, Amadou C, Brun H, Rouillon V, McLaren F, Le Rolle AF, Graham M, Butcher GW, Joly E - BMC Immunol. (2003)

Molecular modelling of RT1-E2u was carried out on the Swiss model server . The coordinates of 1ED3, 1QLF, 1HOC and 1CE6 were used by the server as templates to generate this model. The software Swiss PDB viewer was used to compare the resulting structure with those of RT1-Aa (1ED3), H2-Ld (1LDP) and H2-Qa2 (1K8D). Acidic residues are represented in red, basic in blue, and hydrophobic in yellow.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC183868&req=5

Figure 9: Molecular modelling of RT1-E2u was carried out on the Swiss model server . The coordinates of 1ED3, 1QLF, 1HOC and 1CE6 were used by the server as templates to generate this model. The software Swiss PDB viewer was used to compare the resulting structure with those of RT1-Aa (1ED3), H2-Ld (1LDP) and H2-Qa2 (1K8D). Acidic residues are represented in red, basic in blue, and hydrophobic in yellow.
Mentions: The Qa2 molecules have been shown to associate with peptide ligands [58] and to depend on the TAP transporter for their expression at the cell surface [59]. The recent crystallographic resolution of the Qa2 molecule derived from the Q9 locus in combination with a nonameric self peptide revealed a shallow hydrophobic groove, providing a plausible explanation for the relatively promiscuous specificity of this MHC class Ib molecule for peptides [60]. When we used molecular modelling to visualise the peptide binding groove of RT1-E2 molecules, we were struck by the overall similarity of the peptide binding groove with that of H2-Qa2 (Figure 9). Not only do both molecules harbour a very hydrophobic F pocket, but they also carry histidine residues at position 9 and 70, which could, as in H2-Qa2, result in the absence of a C pocket, and in the bulging of peptides out of the middle of the peptide binding groove.

Bottom Line: The RT1n MHC haplotype (found in BN rats) carries a single RT1-E2 locus, which lies in the RT1-C/E region of the MHC and displays the typical exon-intron organisation and promoter features seen in other rat MHC class I genes.Compared to other class I molecules, this suggests that RT1-E2 molecules may associate with well defined sets of ligands.Several characteristics point to a certain similarity to the mouse H2-Qa2 and human HLA-G molecules.

View Article: PubMed Central - HTML - PubMed

Affiliation: IFR Claude de Préval, INSERM U563, CHU Purpan, 31300 Toulouse, France. laupoui@pasteur.fr

ABSTRACT

Background: So-called "immunoprivileged sites" are tissues or organs where slow allograft rejection correlates with low levels of expression of MHC class I molecules. Whilst classical class I molecules are recognised by cytotoxic T lymphocytes (CTL), some MHC class I molecules are called "non-classical" because they exhibit low polymorphism and are not widely expressed. These last years, several studies have shown that these can play different, more specialised roles than their classical counterparts. In the course of efforts to characterise MHC class I expression in rat cells obtained from immunoprivileged sites such as the central nervous system or the placenta, a new family of non-classical MHC class I molecules, which we have named RT1-E2, has been uncovered.

Results: Members of the RT1-E2 family are all highly homologous to one another, and the number of RT1-E2 loci varies from one to four per MHC haplotype among the six rat strains studied so far, with some loci predicted to give rise to soluble molecules. The RT1n MHC haplotype (found in BN rats) carries a single RT1-E2 locus, which lies in the RT1-C/E region of the MHC and displays the typical exon-intron organisation and promoter features seen in other rat MHC class I genes. We present evidence that: i) RT1-E2 molecules can be detected at the surface of transfected mouse L cells and simian COS-7 cells, albeit at low levels; ii) their transport to the cell surface is dependent on a functional TAP transporter. In L cells, their transport is also hindered by protease inhibitors, brefeldin A and monensin.

Conclusions: These findings suggest that RT1-E2 molecules probably associate with ligands of peptidic nature. The high homology between the RT1-E2 molecules isolated from divergent rat MHC haplotypes is particularly striking at the level of their extra-cellular portions. Compared to other class I molecules, this suggests that RT1-E2 molecules may associate with well defined sets of ligands. Several characteristics point to a certain similarity to the mouse H2-Qa2 and human HLA-G molecules.

Show MeSH