期刊
JOURNAL OF IMMUNOLOGY
卷 183, 期 8, 页码 5397-5406出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0901460
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资金
- Swiss National Center of Competence in Research (NCCR) Molecular Oncology
- Ludwig Institute for Cancer Research, NY
- Swiss National Science Foundation [3200B0-118123/1]
- Oncosuisse [OCS-01995-02-2007]
- Wilhelm Sander-Foundation (Germany)
- EU
Immunotherapy of cancer is often performed with altered analog peptide Ags optimized for HLA class I binding, resulting in enhanced immunogenicity, but the induced T cell responses require further evaluation. Recently, we demonstrated fine specificity differences and enhanced recognition of naturally presented Ag by T cells after vaccination with natural Melan-A/MART-1 peptide, as compared with analog peptide. In this study, we compared the TCR primary structures of 1489 HLA-A*0201/Melan-A(26-35)-specific CD8 T cells derived from both cohorts of patients. Although a strong preference for TRAV12-2 segment usage was present in nearly all patients, usage of particular TRAJ gene segments and CDR3 alpha composition differed slightly after vaccination with natural vs analog peptide. Moreover, TCR beta-chain repertoires were broader after natural than analog peptide vaccination. In all patients, we observed a marked conservation of the CDR3 beta amino acid composition with recurrent sequences centered on a glycyl-leucyl/valyi/alanyl-glycyl motif. In contrast to viral-specific TCR repertoires, such public motifs were primarily expressed by nondominant T cell clonotypes, which contrasted with private CDR3 beta signatures frequently found in T cell clonotypes that dominated repertoires of individual patients. Interestingly, no differences in functional avidity were observed between public and private T cell clonotypes. Collectively, our data indicate that T cell repertoires generated against natural or analog Melan-A peptide exhibited slightly distinct but otherwise overlapping and structurally conserved TCR features, suggesting that the differences in binding affinity/avidity of TCRs toward pMHC observed in the two cohorts of patients are caused by subtle structural TCR variations. The Journal of Immunology, 2009, 183: 5397-5406.
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