Germ line-governed recognition of a cancer epitope by an immunodominant human T-cell receptor.
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 alpha (TCRalpha) 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.
Cole
David K
DK
Department of Infection, Immunity, and Biochemistry, Henry Wellcome Building, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
Yuan
Fang
F
Rizkallah
Pierre J
PJ
Miles
John J
JJ
Gostick
Emma
E
Price
David A
DA
Gao
George F
GF
Jakobsen
Bent K
BK
Sewell
Andrew K
AK
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000737:chemistry; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005854:Germ Cells / Q000276:immunology*; D015234:HLA-A Antigens / Q000276:immunology; D015789:HLA-A2 Antigen; D006801:Humans; D007113:Immunity, Innate; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology*; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology*; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000737:chemistry; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D012995:Solubility; D013379:Substrate Specificity; D013816:Thermodynamics
D000951:Antigens, Neoplasm; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell