Dominant TCR-{alpha} Requirements for a Self Antigen Recognition in Humans

• Published in: The Journal of immunology (1950) 2002-12, Vol.169 (11), p.6253-6260
• Main Authors: Mantovani, Stefania, Palermo, Belinda, Garbelli, Silvia, Campanelli, Rita, Robustelli della Cuna, Gioacchino, Gennari, Roberto, Benvenuto, Federica, Lantelme, Erica, Giachino, Claudia
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606

TCR-[alpha] and -[beta] chains are composed of somatically rearranged V, D, and J germline-encoded gene segments that confer Ag specificity. Recent crystallographic analyses revealed that TCR-[alpha] has more contacts with peptide than TCR-[beta], suggesting the possibility that peptide recognition predominantly relies on TCR-[alpha]. T cells specific for the self Ag Melan-A /MART-1 possess an exceptionally high precursor frequency in human histocompatibility leukocyte Ag-A2 individuals. This provided a unique situation for assessment of the structural relationship between TCR and peptide/MHC ligand at both the pre- and postimmune levels. Molecular and phenotypic analysis of many different Melan-A-specific T cell populations revealed that a structural constraint is imposed on the TCR for engagement with Melan-A peptides presented by HLA-A2, namely the highly preferential use of a particular TCRAV segment, AV2. Examination of CD8 single-positive thymocytes indicated that this preferential use in forming the Melan-A-specific TCR is mainly imposed by intrathymic positive selection. Our data demonstrate a dominant function of TCRAV2 segment in forming the TCR repertoire specific for the human self Ag Melan-A/MART-1 and support the view that Ag recognition is mediated predominantly by TCR-[alpha].