Ligand motif of the autoimmune disease-associated mouse MHC class II molecule H2-A(S)

The MHC class II molecule H2-A(s), expressed in the SJL mouse strain, is th e principle restriction element of autoreactive CD4(+) T cells mediating ex perimental autoimmune encephalomyelitis, an animal model of multiple sclero sis. We deduced the H2-A(s) ligand motif from the analysis of naturally pro cessed self peptides and from peptide binding studies. Major anchor residue s were identified using various sets of substituted and truncated peptides, derived from natural peptide ligands and known H2-A(s) binders like myelin basic protein 81-99. The nine-residue H2-A(s) core binding motif comprises an arrangement of anchors in relative positions P1, P4, P6, P7, and P9. Th e P1 pocket is relatively unspecific and the P6 pocket favors hydrophobic-a liphatic side chains. The P1 pocket contributes little to peptide binding. Primary anchors were identified in P4, P7, and in particular in P9. The pre ferred anchor residues are Lys (P4), His/Arg (P7), and Pro (P9), respective ly. Ala-polysubstituted peptides containing only one of these dominant anch or residues still retain the capacity to bind to H2-AS. Thus, the presence of only one suitable anchor side chain in P4, P7, or P9 is sufficient for h igh-affinity peptide binding, at least in the absence of negatively charged side chains nearby. The identified ligand motif facilitates the analysis o f immunogenic peptides interacting with H2-AS and will allow a better predi ction of pathogenetically relevant peptide antigens in the autoimmune mouse model.