Prevalent role of TCR alpha-chain in the selection of the preimmune repertoire specific for a human tumor-associated self-antigen

J Immunol. 2003 May 15;170(10):5103-9. doi: 10.4049/jimmunol.170.10.5103.


The specificity of recognition of pMHC complexes by T lymphocytes is determined by the V regions of the TCR alpha- and beta-chains. Recent experimental evidence has suggested that Ag-specific TCR repertoires may exhibit a more V alpha- than V beta-restricted usage. Whether V alpha usage is narrowed during immune responses to Ag or if, on the contrary, restricted V alpha usage is already defined at the early stages of TCR repertoire selection, however, has remained unexplored. Here, we analyzed V and CDR3 TCR regions of single circulating naive T cells specifically detected ex vivo and isolated with HLA-A2/melan-A peptide multimers. Similarly to what was previously observed for melan-A-specific Ag-experienced T cells, we found a relatively wide V beta usage, but a preferential V alpha 2.1 usage. Restricted V alpha 2.1 usage was also found among single CD8(+) A2/melan-A multimer(+) thymocytes, indicating that V alpha-restricted selection takes place in the thymus. V alpha 2.1 usage, however, was independent from functional avidity of Ag recognition. Thus, interaction of the pMHC complex with selected V alpha-chains contributes to set the broad Ag specificity, as underlined by preferential binding of A2/melan-A multimers to V alpha 2.1-bearing TCRs, whereas functional outcomes result from the sum of these with other interactions between pMHC complex and TCR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antigens, Neoplasm
  • Autoantigens / genetics
  • Autoantigens / immunology*
  • Autoantigens / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Clone Cells
  • Cytotoxicity, Immunologic / genetics
  • Epitopes, T-Lymphocyte / biosynthesis
  • Epitopes, T-Lymphocyte / genetics
  • Epitopes, T-Lymphocyte / immunology*
  • Epitopes, T-Lymphocyte / metabolism
  • Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor / physiology*
  • Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / physiology
  • HLA-A2 Antigen / biosynthesis
  • HLA-A2 Antigen / genetics
  • HLA-A2 Antigen / immunology*
  • HLA-A2 Antigen / metabolism
  • Hematopoietic Stem Cells / immunology
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • MART-1 Antigen
  • Melanoma / genetics
  • Melanoma / immunology*
  • Molecular Sequence Data
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology*
  • Neoplasm Proteins / metabolism
  • RNA, Messenger / analysis
  • Receptors, Antigen, T-Cell, alpha-beta / biosynthesis
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, alpha-beta / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism
  • Tumor Cells, Cultured


  • Antigens, Neoplasm
  • Autoantigens
  • Epitopes, T-Lymphocyte
  • HLA-A2 Antigen
  • MART-1 Antigen
  • MLANA protein, human
  • Neoplasm Proteins
  • RNA, Messenger
  • Receptors, Antigen, T-Cell, alpha-beta