Prevalent role of TCR alpha-chain in the selection of the preimmune repertoire specific for a human tumor-associated self-antigen |
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Authors: | Dietrich Pierre-Yves Le Gal Frédérique-Anne Dutoit Valérie Pittet Mikäel J Trautman Lydie Zippelius Alfred Cognet Isabelle Widmer Valérie Walker Paul R Michielin Olivier Guillaume Philippe Connerotte Thierry Jotereau Francine Coulie Pierre G Romero Pedro Cerottini Jean-Charles Bonneville Marc Valmori Danila |
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Institution: | Division of Oncology, Laboratory of Tumor Immunology, University Hospital, Geneva, Switzerland. pierre-yves.dietrich@hcuge.ch |
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Abstract: | 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. |
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