A small number of residues in the class II molecule I-A(u) confer the ability to bind the myelin basic protein peptide Ac1-11

The N-terminal peptide Ac1-11 of myelin basic protein induces experimental autoimmune encephalomyelitis in H-2(u) and (H-2(u) × H-2(s)) mice but does not in H-2(s) mice. Ac1-11 binds weakly to the class II major histocompatibility complex (MHC) molecule I-A(u) but not at all to I-A(s). We have studied the interaction of Ac1-11 and I-A(u) as a model system for therapeutic intervention in the autoimmune response seen in experimental autoimmune encephalomyelitis. Two polymorphic residues that differ between I-A(u) and I-A(s), Y26β and T28β, and one conserved residue, E74β, confer specific binding of Ac1-11 to I-A(u). A fourth residue, R70β in I-A(u), affects both peptide binding and T cell recognition. These results are consistent with a model that places arginine at position five of Ac1-11 in pockets 4 and 7 of the MHC groove, which is formed in part by residues 26, 28, 70, and 74 of Aβ(u) and places lysine at position four of Ac1-11, previously shown to be a major MHC contact, in hydrophobic pocket 6. The data indicate that the primary region of I-A(u) that confers specific binding of Ac1-11 lies in the center of the peptide binding groove rather than in the region that contacts the N terminus of the peptide, as has been shown for HLA DR and the homologous I-E molecules.