Diversity of the fine specificity displayed by HLA-A*0201-restricted CTL specific for the immunodominant Melan-A/MART-1 antigenic peptide

Details

Serval ID
serval:BIB_01902E153C0B
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Diversity of the fine specificity displayed by HLA-A*0201-restricted CTL specific for the immunodominant Melan-A/MART-1 antigenic peptide
Journal
Journal of Immunology
Author(s)
Valmori  D., Gervois  N., Rimoldi  D., Fonteneau  J. F., Bonelo  A., Lienard  D., Rivoltini  L., Jotereau  F., Cerottini  J. C., Romero  P.
ISSN
0022-1767 (Print)
Publication state
Published
Issued date
12/1998
Volume
161
Number
12
Pages
6956-62
Notes
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Dec 15
Abstract
HLA-A*0201 melanoma patients often develop a CTL response to an immunodominant peptide derived from the melanocyte lineage-specific protein Melan-A/MART-1. We have shown previously that the antigenic peptide most often involved is the decapeptide Melan-A(26-35) (EAAGIGILTV). We also observed some clonal diversity in the fine specificity of Melan-A-specific CTL. To substantiate this observation, we have now tested a series of Melan-A(26-35) variant peptides containing single alanine substitutions for binding to HLA-A*0201 and recognition by polyclonal and monoclonal Melan-A-specific CTL. Substitution of several residues with alanine reduced peptide binding activity by > 10-fold. In contrast, substitution of E26 with alanine (AAAGIGILTV) resulted in a 5-fold higher binding activity as well as in stronger stability of the corresponding HLA-A*0201/peptide complexes. Interestingly, the peptide variant AAAGIGILTV was recognized more efficiently than the natural decapeptide by short term cultured, tumor-infiltrated lymph node cell cultures and a number of Melan-A-specific CTL clones derived from different individuals. Moreover, this analysis revealed that the fine specificity of the CTL response to the Melan-A immunodominant epitope is quite diverse at the clonal level. At least three distinct patterns of fine specificity were identified. This diversity appears to reflect the diversity of the TCR repertoire available for this Ag, since similar results were obtained with a panel of Melan-A-specific CTL clones derived from a single melanoma patient. These findings have important implications for the formulation of Melan-A peptide-based vaccines as well as for the monitoring of Melan-A-specific CTL responses in melanoma patients.
Keywords
Alleles Amino Acid Substitution Antigens, Neoplasm/chemistry/*immunology Cell Line, Transformed Cells, Cultured Gene Rearrangement, T-Lymphocyte HLA-A2 Antigen/genetics/*immunology Humans Immunodominant Epitopes/chemistry/*immunology Lymphocytes, Tumor-Infiltrating/immunology Melanoma/*immunology Neoplasm Proteins/chemistry/*immunology Peptide Fragments/chemistry/*immunology Protein Binding T-Lymphocytes, Cytotoxic/*immunology Tumor Cells, Cultured
Pubmed
Web of science
Create date
28/01/2008 11:14
Last modification date
20/08/2019 12:23
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