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

Eur J Immunol. 2014 Sep;44(9):2811-21. doi: 10.1002/eji.201444499. Epub 2014 Aug 18.


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-1(26(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 TCRα- and TCRβ- chains derived from HLA-A2-MART-1(26-35) -specific CD8(+) T-cell clones is unusually permissive in conferring MART-1 specificity, provided the CDR1α TRAV12-2 region is used. Whether TCR bias alone accounts for the unusual abundance of HLA-A2-MART-1(26-35) -specific CD8(+) T cells has remained conjectural. Here, we provide an alternative explanation: misinitiated transcription of the MART-1 gene resulting in truncated mRNA isoforms leads to lack of promiscuous transcription of the MART-1(26-35) epitope in human medullary thymic epithelial cells and, consequently, evasion of central self-tolerance toward this epitope. Thus, biased TCR usage and leaky central tolerance might act in an independent and additive manner to confer high frequency of MART-1(26-35) -specific CD8(+) T cells.

Keywords: Central tolerance; Human medullary thymic epithelial cells; MART-1; Melanoma; Promiscuous gene expression.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Line
  • Epithelial Cells / cytology
  • Epithelial Cells / immunology*
  • Epitopes, T-Lymphocyte / immunology*
  • Female
  • HLA-A2 Antigen / immunology
  • Humans
  • MART-1 Antigen / immunology*
  • Male
  • Receptors, Antigen, T-Cell, alpha-beta / immunology
  • Thymus Gland / cytology
  • Thymus Gland / immunology*
  • Transcription Initiation, Genetic / immunology*


  • Epitopes, T-Lymphocyte
  • HLA-A2 Antigen
  • MART-1 Antigen
  • MLANA protein, human
  • Receptors, Antigen, T-Cell, alpha-beta