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Fine structural variations of alphabetaTCRs selected by vaccination with natural versus altered self-antigen in melanoma patients.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2009 Oct 15; Vol. 183 (8), pp. 5397-406. Date of Electronic Publication: 2009 Sep 28. - Publication Year :
- 2009
-
Abstract
- 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 CDR3alpha 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 CDR3beta amino acid composition with recurrent sequences centered on a glycyl-leucyl/valyl/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" CDR3beta 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.
- Subjects :
- Amino Acid Sequence
Antigens, Neoplasm therapeutic use
Autoantigens therapeutic use
Base Sequence
Cancer Vaccines therapeutic use
HLA-A Antigens immunology
HLA-A2 Antigen immunology
Humans
Immunotherapy
MART-1 Antigen
Melanoma immunology
Molecular Sequence Data
Neoplasm Proteins therapeutic use
Prospective Studies
Protein Conformation
Receptors, Antigen, T-Cell, alpha-beta immunology
Sequence Alignment
Skin Neoplasms immunology
Antigens, Neoplasm immunology
Autoantigens immunology
CD8-Positive T-Lymphocytes immunology
Cancer Vaccines immunology
Melanoma therapy
Neoplasm Proteins immunology
Receptors, Antigen, T-Cell, alpha-beta chemistry
Skin Neoplasms therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 183
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 19786555
- Full Text :
- https://doi.org/10.4049/jimmunol.0901460