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-Chain in the Selection of the Preimmune Repertoire Specific for a Human Tumor-Associated Self-Antigen1
* Division of Oncology, Laboratory of Tumor Immunology, University Hospital, Geneva, Switzerland;
Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, University Hospital, Lausanne, Switzerland;
Institut National de la Santé et de la Recherche Médicale, Unité 463, Institut de Biologie, Nantes, France;
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland; and
¶ Cellular Genetics Unit, Université Catholique de Louvain, Brussels, Belgium
The specificity of recognition of pMHC complexes by T lymphocytes is determined by the V regions of the TCR 
- and 
-chains. Recent experimental evidence has suggested that Ag-specific TCR repertoires may exhibit a more V- than V-restricted usage. Whether V usage is narrowed during immune responses to Ag or if, on the contrary, restricted V 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 usage, but a preferential V 2.1 usage. Restricted V 2.1 usage was also found among single CD8+ A2/melan-A multimer+ thymocytes, indicating that V-restricted selection takes place in the thymus. V 2.1 usage, however, was independent from functional avidity of Ag recognition. Thus, interaction of the pMHC complex with selected V-chains contributes to set the broad Ag specificity, as underlined by preferential binding of A2/melan-A multimers to V 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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