A molecular basis for how a single TCR interfaces multiple ligands.

Boesteanu A, Brehm M, Mylin LM, Christianson GJ, Tevethia SS, Roopenian DC, Joyce S
J Immunol. 1998 161 (9): 4719-27

PMID: 9794402

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.

MeSH Terms (20)

Amino Acid Sequence Animals Antigen Presentation Antigens Epitopes H-2 Antigens Ligands Mice Mice, Inbred BALB C Mice, Inbred C57BL Models, Immunological Models, Molecular Molecular Sequence Data Peptide Fragments Peptide Library Protein Binding Protein Conformation Receptors, Antigen, T-Cell Structure-Activity Relationship T-Lymphocytes, Cytotoxic

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