Sequence features that correlate with MHC restriction

Identification of common sequence motifs in antigenic peptides restricted to a specific class II molecule has not been easy due to the large variation in length and sequence that is observed in these peptides. The goal of this study is to develop an automated computerized method for the identification of sequence features and structural determinants that play a role in the MHC restriction of helper T-cell antigenic peptides. For this, we compiled an extended database of helper T-cell sites, including the information on MHC restriction, when available. Two groups of peptides are assigned to each MHC type: (1) peptides that bind to that MHC molecule to elicit a T-cell response, and (2) peptides that were shown experimentally either not to bind to or not to elicit a T-cell proliferative response in association with that MHC molecule. We search for common motifs in the group of binding peptides, and identify significant motifs that are frequent among these peptides but almost absent in the group of non-binding peptides. A motif consists of physical-chemical and structural properties that may be responsible for binding specificity and can be extracted from sequence data, such as, hydrophobicity, charge, hydrogen bonding capability, etc. The first search is performed on the non-aligned binding peptides. Next, the sequences are aligned according to an identified motif and a search for additional, conserved, properties is performed. The statistical significance of the motifs is evaluated as well as their compatibility with published experimental results on substitution effects. Here we demonstrate the general scheme of the analysis and results for I-Ek and I-Ak associated peptides.