MHC class II Ab diabetogenic residue 57 Asp/non-Asp dimorphism influences T-cell recognition and selection

Human and mouse major histocompatibility complex class II beta chain alleles associated with predisposition to type I diabetes often encode a non-charged residue at position 57 rather than the negatively charged aspartate residue characteristic of non-susceptible haplotypes. The mechanism(s) whereby this polymorphism promotes eventual pancreatic beta cell destruction is unclear. The type I diabetes-susceptible mouse strain NOD (H2(g7)) encodes serine at Ab position 57 and is one of the few mouse class II molecules not encoding aspartate at this position. To gain insight into the structural impact of this amino acid substitution and any influence it may have on T-cell selection, we assessed whether T-cell repertoires selected by diabetogenic class II (A(g7)) are tolerant of mutant Ab (residues 56 and 57) H2-A(g7). We find that NOD mice mount an allogeneic response to skin grafts expressing mutant position 57 (serine to aspartate) Ab(g7); but not to grafts expressing mutant position 56 (histidine to proline) Ab(g7). Graft rejection correlates with the presence of CD4+ T cells specific for the mutant H2-A(g7) heterodimer. Genetic analyses are consistent with Ab position 57 aspartate/non-aspartate dimorphism influencing peptide selection and hence repertoire selection. Direct evidence for the serine to aspartate substitution at position 57 influencing T-cell selection is found by analysis of peripheral T-cell receptor (TCR) usage and the CD4/CD8 T-cell ratio.