How H13 Histocompatibility Peptides Differing by a Single Methyl Group and Lacking Conventional MHC Binding Anchor Motifs Determine Self-Nonself Discrimination

Abstract

The mouse H13 minor histocompatibility (H) Ag, originally detected as a barrier to allograft transplants, is remarkable in that rejection is a consequence of an extremely subtle interchange, P4Val/Ile, in a nonamer H2-Db-bound peptide. Moreover, H13 peptides lack the canonical P5Asn central anchor residue normally considered important for forming a peptide/MHC complex. To understand how these noncanonical peptide pMHC complexes form physiologically active TCR ligands, crystal structures of allelic H13 pDb complexes and a P5Asn anchored pDb analog were solved to high resolution. The structures show that the basis of TCRs to distinguish self from nonself H13 peptides is their ability to distinguish a single solvent-exposed methyl group. In addition, the structures demonstrate that there is no need for H13 peptides to derive any stabilization from interactions within the central C pocket to generate fully functional pMHC complexes. These results provide a structural explanation for a classical non-MHC-encoded H Ag, and they call into question the requirement for contact between anchor residues and the major MHC binding pockets in vaccine design.

Endoplasmic Reticulum Aminopeptidase Associated with Antigen Processing Regulates Quality of Processed Peptides Presented by MHC Class I Molecules

“…The susceptibility of the SVL9 peptide to destruction by ERAAP correlates inversely with the ability of this peptide to bind D b . This is remarkably consistent with previous results showing that the SVL9 peptide was bound weakly by D b and binding could be improved by replacing the p5 glycine in SVL9 with the canonical p5 asparagine anchor residue (16). Indeed substituting the p5 glycine with the asparagine residue in the SVNL9 peptide improved both the D b binding and reduced the susceptibility to destruction by ERAAP.…”

Recognition of allo-peptide is governed by novel anchor imposition and limited variations in TCR contact residues

“…Antigenic peptides from mH-Ags have served as useful models to understand antigen processing and presentation (Spierings et al, 2003;Engelhard et al, 2002;Malarkannan et al, 1999), immunodominance (van Els et al, 1992;Wolpert et al, 1998;Choi et al, 2002), graft rejections (Korngold and Sprent, 1983), GvL (Spierings et al, 2003;Mutis et al, 2002;Riddell et al, 2002;Nishida et al, 2004), and structural analyses of TCR-peptide/MHC interactions (Ostrov et al, 2002). H7 is one of the classical mH-Ag that was originally defined by Snell.…”

“…The H13 peptide that is also presented on D b MHC contains a glycine at p5 instead of the canonical asparagine or arginine (SSVVGVWYL). In this case, the peptide binding occurs with the help of a water molecule, which stabilizes the peptide and the MHC in the absence of either direct or hydrogen bonding (Ostrov et al, 2002). Similarly, H47-derived peptide, SCILLYIVI, lacks a defined central anchor residue; however the mechanism that helps in its binding to D b MHC is yet to be elucidated.…”

“…In contrast, how a buried aspartic acid in KDL9/D b (H7b) creates contact with the TCR is not yet clear. It is likely that p7 is solvent-accessible as shown in the crystal structures of H13 peptides/D b complexes (Ostrov et al, 2002). Crystallographic structures in association with peptide/MHC complexes have provided evidence that TCR binding can distort the peptide confirmation on the MHC (Garboczi et al, 1996).…”

The H4b Minor Histocompatibility Antigen Is Caused by a Combination of Genetically Determined and Posttranslational Modifications

“…Variant peptides, when presented by the donor class I molecule that is identical with that of the recipient, appear nonself to the host. Differences as subtle as a loss of a methylene group in a TCR contact residue are sufficient to elicit a CTL response (10,12), which then culminates in allograft rejection. Thus, minor H Ags are highly immunogenic.…”