Article: article from journal or magazin.
Prevalent role of TCR alpha-chain in the selection of the preimmune repertoire specific for a human tumor-associated self-antigen.
Journal of Immunology
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
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.
Amino Acid Sequence, Antigens, Neoplasm, Autoantigens/genetics, Autoantigens/immunology, Cell Differentiation/genetics, Cell Differentiation/immunology, Clone Cells, Cytotoxicity, Immunologic/genetics, Epitopes, T-Lymphocyte/biosynthesis, Epitopes, T-Lymphocyte/genetics, 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, Hematopoietic Stem Cells/immunology, Hematopoietic Stem Cells/metabolism, Humans, Melanoma/genetics, Melanoma/immunology, Molecular Sequence Data, Neoplasm Proteins/genetics, Neoplasm Proteins/immunology, RNA, Messenger/analysis, Receptors, Antigen, T-Cell, alpha-beta/biosynthesis, Receptors, Antigen, T-Cell, alpha-beta/genetics, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes, Cytotoxic/immunology, T-Lymphocytes, Cytotoxic/metabolism, Tumor Cells, Cultured
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