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Elsevier, Journal of Biological Chemistry, 40(284), p. 27281-27289, 2009

DOI: 10.1074/jbc.m109.022509

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

Journal article published in 2009 by David K. Cole, Fang Yuan, Pierre J. Rizkallah, John J. Miles ORCID, Emma Gostick, David A. Price, George F. Gao, Bent K. Jakobsen, Andrew K. Sewell ORCID
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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.