Redistribution of critical major histocompatibility complex and T cell receptor-binding functions of residues in an antigenic sequence after biterminal substitution

Residues critical for establishing a trimolecular interaction with
a major histocompatibility complex (MHC)-encoded receptor and a T
cell antigen receptor (TcR) were determined for an antigenic
nonapeptide. The N-terminal residue proved to be involved in
binding of the peptide to both receptors and the C-terminal residue
was essential for MHC binding. While substitution of either of
these critical terminal residues by alanine resulted in an almost
complete loss of peptide antigenicity, simultaneous substitution of
both created a new functional ligand for the same MHC molecule and
the same TcR. Notably, in the biterminally substituted peptide, the
core residues took on new roles in the trimolecular interaction in
that a residue critical in the authentic nonapeptide for TcR
binding became critical for MHC binding and former spacer residues
became essential to various degrees for the interaction with either
receptor or both. Thus, apparently, the loss of the terminal
residues' contribution was at least partially compensated by a
redistribution of the roles among the remaining residues. These
results reflect a cooperative contribution of all residues of an
antigenic peptide to its binding to both receptors and thus
challenge a static definition of agretope and epitope as MHC and
TcR binding sites.