Germ Line-governed Recognition of a Cancer Epitope by an Immunodominant Human T-cell Receptor

• Published in: The Journal of biological chemistry Vol. 284; no. 40; pp. 27281 - 27289
• Main Authors: Cole, David K., Yuan, Fang, Rizkallah, Pierre J., Miles, John J., Gostick, Emma, Price, David A., Gao, George F., Jakobsen, Bent K., Sewell, Andrew K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02-10-2009; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Sequence; Antigens, Neoplasm - chemistry; CD8-Positive T-Lymphocytes - immunology; Germ Cells - immunology; HLA-A Antigens - immunology; HLA-A2 Antigen; Humans; Immunity, Innate; Immunodominant Epitopes - chemistry; Immunodominant Epitopes - immunology; MART-1 Antigen; Melanoma - immunology; Models, Molecular; Neoplasm Proteins - chemistry; Protein Conformation; Protein Structure and Folding; Receptors, Antigen, T-Cell - chemistry; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Solubility; Substrate Specificity; Thermodynamics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.022509

CD8+ T-cells specific for MART-1-(26–35), a dominant melanoma epitope restricted by human leukocyte antigen (HLA)-A*0201, are exceptionally common in the naive T-cell repertoire. Remarkably, the TRAV12-2 gene is used to encode the T-cell receptor α (TCRα) chain in >87% of these T-cells. Here, the molecular basis for this genetic bias is revealed from the structural and thermodynamic properties of an archetypal TRAV12-2-encoded TCR complexed to the clinically relevant heteroclitic peptide, ELAGIGILTV, bound to HLA-A*0201 (A2-ELA). Unusually, the TRAV12-2 germ line-encoded regions of the TCR dominate the major atomic contacts with the peptide at the TCR/A2-ELA interface. This “innate” pattern of antigen recognition probably explains the unique characteristics and extraordinary frequencies of CD8+ T-cell responses to this epitope.