Positive selection of the T-cell repertoire is affected by mutations in the peptide-binding site of MHC class I molecules.

H-2Kb mutant molecules (H-2Kbm) and the H-2Kb-restricted response to OVA and VSV N peptides were used to investigate the influence of polymorphism of structurally defined regions of the MHC class I molecules on intrathymic positive selection of the T-cell repertoire. We show that the positive selection of the T-cell repertoire in the thymus requires the self-peptide to be present in the MHC antigen-binding site. A correlation between the ability of four MHC molecules to present antigenic peptide and to positively select T cells specific for it was noted. The self-peptides involved in positive selection may therefore mimic the foreign peptide during intrathymic selection. A structural correlate of this mimicry may be a similar or identical binding requirement for the antigen-binding pocket(s)/residues of the MHC peptide-binding site.