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-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.
Division of Developmental Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Sheena
S
Pinto
Daniel
D
Sommermeyer
Chloé
C
Michel
Susanne
S
Wilde
Dolores
D
Schendel
Wolfgang
W
Uckert
Thomas
T
Blankenstein
Bruno
B
Kyewski
D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D058965:MART-1 Antigen / Q000276:immunology*; D008297:Male; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D061785:Transcription Initiation, Genetic / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; C548667:MLANA protein, human; D016693:Receptors, Antigen, T-Cell, alpha-beta
Central tolerance; Human medullary thymic epithelial cells; MART-1; Melanoma; Promiscuous gene expression