A molecular basis for how a single TCR interfaces multiple ligands.
Animal, Antigen-Presentation, Antigens: im, me, Epitopes: im, me, H-2-Antigens: im, Ligands, Mice, Mice-Inbred-BALB-C, Mice-Inbred-C57BL, Models-Immunological, Models-Molecular, Molecular-Sequence-Data, Peptide-Fragments: im, me, Peptide-Library, Protein-Binding, Protein-Conformation, Receptors-Antigen-T-Cell: me, Structure-Activity-Relationship, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S, T-Lymphocytes-Cytotoxic: im
J Immunol 1998 Nov 1;161(9):4719-27
CA60395/CA/NCI, AI34070/AI/NIAID, CA25000/CA/NCI
CD8+ T cells respond to Ags when their clonotypic receptor, the TCR, recognizes nonself peptides displayed by MHC class I molecules. The TCR/ligand interactions are degenerate because, in its life time, the TCR interacts with self MHC class I-self peptide complexes during ontogeny and with self class I complexed with nonself peptides to initiate Ag-specific responses. Additionally, the same TCR has the potential to interact with nonself class I complexed with nonself peptides. How a single TCR interfaces multiple ligands remains unclear. Combinatorial synthetic peptide libraries provide a powerful tool to elucidate the rules that dictate how a single TCR engages multiple ligands. Such libraries were used to probe the requirements for TCR recognition by cloned CD8+ T cells directed against Ags presented by H-2Kb class I molecules. When H-2Kb contact residues were examined, position 3 of the peptides proved more critical than the dominant carboxyl-terminal anchor residue. Thus, secondary anchor residues can play a dominant role in determining the antigenicity of the epitope presented by class I molecules. When the four solvent-exposed potential TCR contact residues were examined, only one or two of these positions required structurally similar residues. Considerable structural variability was tolerated at the remaining two or three solvent-exposed residues of the Kb-binding peptides. The TCR, therefore, requires close physico-chemical complementarity with only a few amino acid residues, thus explaining why TCR/MHC interactions are of low affinity and degenerate.
Boesteanu, A; Brehm, M; Mylin, L M.; Christianson, G J.; Tevethia, S S.; Roopenian, D C.; and Joyce, S, " A molecular basis for how a single TCR interfaces multiple ligands." (1998). Faculty Research 1990 - 1999. 1126.
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