Misinitiation of intrathymic MART-1 transcription and biased TCR usage explain the high frequency of MART-1-specific T cells

Immunity to tumor differentiation antigens, such as melanoma antigen recognized by T cells 1 (MART-1), has been comprehensively studied. Intriguingly, CD8(+) T cells specific for the MART-126(27)-35 epitope in the context of HLA-A0201 are about 100 times more abundant compared with T cells specific for other tumor-associated antigens. Moreover, MART-1-specific CD8(+) T cells show a highly biased usage of the Vα-region gene TRAV12-2. Here, we provide independent support for this notion, by showing that the combinatorial pairing of different TCR{alpha}- and TCR{beta}- chains derived from HLA-A2-MART-126 -35 -specific CD8(+) T-cell clones is unusually permissive in conferring MART-1 specificity, provided the CDR1{alpha} TRAV12-2 region is used. Whether TCR bias alone accounts for the unusual abundance of HLA-A2-MART-126 -35 -specific CD8(+) T cells has remained conjectural. Here, we provide an alternative explanation: mis-initiated transcription of the MART-1 gene resulting in truncated mRNA isoforms leads to lack of promiscuous transcription of the MART-126 -35 epitope in human medullary thymic epithelial cells and, consequently, evasion of central self-tolerance towards this epitope. Thus, biased TCR usage and leaky central tolerance might act in an independent and additive manner to confer high frequency of MART-126 -35 -specific CD8(+) T cells.