Peptide presentation by class-I major histocompatibility complex molecules.
MHC class-I molecules express distinct peptide-binding pockets within their antigen-binding groove. These are critically involved in the binding of antigenic peptides. The amino acid composition of a pocket dictates the structure of a peptide which can be bound in it. This is evident as a consensus amino acid motif which has to exist within a peptide in order for it to bind to a particular MHC allele. Perturbation of a MHC pocket by amino acid substitution can result in the abolition of peptide binding. Less drastic mutations of the peptide-binding groove, particularly the ones away from the critical pocket, can subtly alter the conformation of bound peptide. Both types of substitution exert an influence on the TCR recognition of antigenic peptide. Peptides are also critically involved in the positive selection of the class-I-restricted TCR repertoire in the thymus. These self peptides act by mimicking their foreign antigens. This mimicking involves the binding of self peptides and foreign antigenic peptides to the same pockets of the MHC class-I-antigen binding groove. Consequently, MHC class-I polymorphism in the antigen binding groove controls the intrathymic positive selection and peripheral antigen presentation by the same mechanisms. The majority of positively selecting self peptides could well originate from the extracellular processing of circulating self proteins. Using the diverse, extracellularly generated self peptides and the different determinant density requirements for positive versus negative selection, the immune system can ensure the repertoire diversity, avoiding both the massive clonal deletion of the selected repertoire and the autoreactivity of its T cells.
Nikolić-Zugić
J
J
Department of Immunology, Research Institute of Scripps Clinic, La Jolla, Calif.
Carbone
F R
FR
D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism*; D000941:Antigens / Q000276:immunology* / Q000378:metabolism; D001665:Binding Sites; D005805:Genes, MHC Class I; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology
D000941:Antigens; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell