Critical residue combinations dictate peptide presentation by MHC class II molecules.

Peptides encompassing the core hen egg lysozyme HEL(52-61) peptide elongated or not and substituted or not with natural and unnatural amino acids were used to find a peptide motif for binding to the major histocompatibility complex (MHC) class II I-Ak. Using a T-cell recognition functional assay, nine out of 10 positions were found to be somehow involved in the I-Ak binding, and six out of 10 residues were involved in T-cell recognition. The deleterious effect of single substitutions could be rescued by changing peptide length and/or sequence. Thus, efficient binding to MHC class II molecules requires not only few anchoring residues correctly interspaced, but a complex, nonrandom combination of residues with appropriate orientation of the peptide backbone and some crucial side chains.