Minors Held by Majors: The H13 Minor Histocompatibility Locus Defined as a Peptide/MHC Class I Complex

Abstract

The products of minor histocompatibility (H) loci are serious barriers to tissue transplantation even among major histocompatibility complex (MHC) identical individuals, frequently causing chronic graft rejection and graft versus host disease. Over 50 minor H loci map to mouse autosomal chromosomes but none are known at the molecular level. By expression cloning, we identified the H13 locus, a classical minor H locus first detected 30 years ago by the trait of graft rejection. The H13a allele is located on chromosome 2 and encodes a novel protein that yields the rare naturally processed nonapeptide SSVVGVWYL (SVL9) for presentation by the Db MHC class I molecule. The SVL9 peptide binds Db MHC despite the absence of the consensus binding motif, and a conservative methyl group substitution (Valine 4 <--> Isoleucine) explains why reciprocal T cell responses are elicited in H13a and H13b congenic strains.

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

“…In contrast, the positively charged basic side chain of arginine is buried deep inside the centrally located anchor pocket of D b MHC, securing KEL9 or KDL9 epitopes within the peptide-binding groove. Absence of the centrally located anchor motifs has been previously reported for two mH-Ag peptides, H13 (Mendoza et al, 1997) and H47 . The H13 peptide that is also presented on D b MHC contains a glycine at p5 instead of the canonical asparagine or arginine (SSVVGVWYL).…”

“…EL4, D b -L cells have been described previously (Mendoza et al, 1997). COS-7 cells were obtained from ATCC.…”

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

“…Most changes resulting in incompatibility are in amino acids that directly interact with critical TCR contact residues (10,11). The results presented herein provide functional evidence for the role of secondary anchor residues, such as those at P3, in altering the antigenicity of the class I-peptide complex.…”

“…5). The data thus far indicate that immune responses to minor H Ags could result from the recipient carrying a null allele (e.g., H60 and HY male Ag) (6,7) or differential or induced expression (e.g., H28) (8), differential processing (e.g., human minor H Ag HA8) (9), or amino acid sequence variation in the peptide epitope (e.g., H3 and H13) (10,11). Sequence variation is a consequence of evolving genomes.…”

“…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.…”