Roles of the Six Peptide-Binding Pockets of the HLA-A2 Molecule in Allorecognition by Human Cytotoxic T-Cell Clones

To evaluate the contribution of the major histocompatibility complex class I pockets to the binding of self-peptides recognized by alloreactive cytotoxic T-lymphocyte (CTL) clones, we have constructed an extensive library of HLA-A2 mutants with different amino acid substitutions in each of the six p...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1993-01, Vol.90 (2), p.674-678
Main Authors: Matsui, Masanori, Hioe, Catarina E., Frelinger, Jeffrey A.
Format: Article
Language:English
Subjects:
Amino acid substitution
Amino acids
Antigens
Biological and medical sciences
Cell Death - immunology
Cell lines
Cellular biology
Clone Cells
Cytotoxicity
Cytotoxicity, Immunologic
DNA Mutational Analysis
Epitopes
Fundamental and applied biological sciences. Psychology
Fundamental immunology
Genes, MHC Class II - genetics
Genetic mutation
Histocompatibility - immunology
Histocompatibility antigens (hla, h-2 and other systems)
HLA-A2 Antigen - genetics
HLA-A2 Antigen - immunology
Humans
Immunity (Disease)
Libraries
Molecular immunology
Molecules
Peptides - metabolism
Reactivity
Structure-Activity Relationship
T lymphocytes
T-Lymphocytes, Cytotoxic - immunology
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Summary:To evaluate the contribution of the major histocompatibility complex class I pockets to the binding of self-peptides recognized by alloreactive cytotoxic T-lymphocyte (CTL) clones, we have constructed an extensive library of HLA-A2 mutants with different amino acid substitutions in each of the six pockets. When these mutants were tested in cytotoxicity assays with a panel of HLA-A2-specific alloreactive CTL clones, each CTL clone showed a unique pattern of reactivity, implying the different contributions of each pocket to binding individual peptides. We noted that the majority of the mutants in pocket B significantly affect recognition by the CTL clones. Unexpectedly, the mutations influencing allorecognition are found in all other pockets as well. Overall, this study demonstrates that each of the six peptide-binding pockets plays an important and distinct role in binding of self-peptides required for recognition of the HLA-A2 molecule by alloreactive CTLs.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.90.2.674