A molecular basis for how a single TCR interfaces multiple ligands.
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
A
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey 17033, USA.
Brehm
M
M
Mylin
L M
LM
Christianson
G J
GJ
Tevethia
S S
SS
Roopenian
D C
DC
Joyce
S
S
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006183:H-2 Antigens / Q000737:chemistry / Q000276:immunology*; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D019151:Peptide Library; D011485:Protein Binding; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000941:Antigens; D000939:Epitopes; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D008024:Ligands; D010446:Peptide Fragments; D019151:Peptide Library; D011948:Receptors, Antigen, T-Cell