Class I major histocompatibility complex anchor substitutions alter the conformation of T cell receptor contacts

An immunogenic peptide (GP2) derived from HER-2/neu binds to HLA-A2.1 very poorly. Some altered-peptide ligands (APL) of GP2 have increased binding af finity and generate improved cytotoxic T lymphocyte recognition of GP2-pres enting tumor cells, but most do not. Increases in binding affinity of singl e-substitution APL are not additive in double-substitution APL. A common fi rst assumption about peptide binding to class I major histocompatibility co mplex is that each residue binds independently. In addition, immunologists interested in immunotherapy frequently assume that anchor substitutions do not affect T cell receptor contact residues. However, the crystal structure s of two GP2 APL show that the central residues change position depending o n the identity of the anchor residue(s), Thus it is clear that subtle chang es in the identity of anchor residues may have significant effects on the p ositions of the T cell receptor contact residues.