Dissecting TCR-MHC/peptide complex interactions with A2/peptide multimers incorporating tumor antigen peptide variants: crucial role of interaction kinetics on functional outcomes.

Details

Serval ID
serval:BIB_49F4F956D23B
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Dissecting TCR-MHC/peptide complex interactions with A2/peptide multimers incorporating tumor antigen peptide variants: crucial role of interaction kinetics on functional outcomes.
Journal
European Journal of Immunology
Author(s)
Dutoit V., Guillaume P., Cerottini J.C., Romero P., Valmori D.
ISSN
0014-2980
Publication state
Published
Issued date
2002
Peer-reviewed
Oui
Volume
32
Number
11
Pages
3285-3293
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Soluble peptide/MHC-class-I (pMHC) multimers have recently emerged as unique reagents for the study of specific interactions between the pMHC complex and the TCR. Here, we assessed the relative binding efficiency of a panel of multimers incorporating single-alanine-substituted variants of the tumor-antigen-derived peptide MAGE-A10(254-262) to specific CTL clones displaying different functional avidity. For each individual clone, the efficiency of binding of multimers incorporating MAGE-A10 peptide variants was, in most cases, in good although not linear correlation with the avidity of recognition of the corresponding variant. In addition, we observed two types of discrepancies between efficiency of recognition and multimer binding. First, for some peptide variants, efficient multimer binding was detected in the absence of measurable effector functions. Some of these peptide variants displayed antagonist activity. Second, when comparing different clones we found clear discrepancies between the dose of peptide required to obtain half-maximal lysis in CTL assays and the binding efficiency of the corresponding multimers. These discrepancies, however, were resolved when the differential stability of the TCR/pMHC complexes was determined. For individual clones, decreased recognition correlated with increased TCR/pMHC off-rate. TCR/pMHC complexes formed by antagonist ligands displayed off-rates faster than those of TCR/pMHC complexes formed with weak agonists. In addition, when comparing different clones, the efficiency of multimer staining correlated better with relative multimer off-rates than with half-maximal lysis values. Altogether, the data presented here reconcile and extend our previous results on the impact of the kinetics of interaction of TCR with pMHC complexes on multimer binding and underline the crucial role of TCR/pMHC off-rates for the functional outcome of such interactions.
Keywords
Antigens, Neoplasm/immunology, Histocompatibility Antigens Class I/metabolism, Humans, Kinetics, Lymphocyte Activation, Neoplasm Proteins/chemistry, Neoplasm Proteins/immunology, Peptide Fragments/immunology, Receptors, Antigen, T-Cell/metabolism, T-Lymphocytes, Cytotoxic/immunology
Pubmed
Web of science
Create date
28/01/2008 12:14
Last modification date
20/08/2019 14:57
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