Role of disulfide bonds in regulating antigen processing and epitope selection.
Knowledge of the events governing Ag processing and epitope selection within APC is key to the development of novel immunotherapeutic strategies for infectious diseases, cancer, and autoimmunity. The influence of disulfides and Ag reduction on the hierarchy of epitope presentation via MHC class II molecules was investigated through studies of a self Ag, IgG kappa. HLA-DR4(+) B cells preferentially present an immunodominant IgG-derived epitope, kappaI, relative to a subdominant kappaII peptide. kappaI contains a cysteine masked within the native Ag via an intrachain disulfide, the latter of which is reduced during Ag processing. Mutagenesis of this cysteine as well as others within kappa minimally perturbed the abundance and overall conformation of IgG. Yet, disruptions in disulfide bonding within this Ag influenced the selective display of class II-restricted dominant and subdominant T cell epitopes. Presentation of the kappaI epitope from both native and variant IgG was dependent upon cellular expression of IFN-gamma-inducible lysosomal thiol reductase. These studies indicate that disulfide bonds regulate Ag processing both locally and at distant sites, thus influencing epitope selection within the class II pathway.
Department of Microbiology and Immunology and Walther Oncology Center, Indiana University School of Medicine, Indianapolis 46202, USA.
Ping
P
Li
M Azizul
MA
Haque
Janice S
JS
Blum
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D002460:Cell Line; D002461:Cell Line, Transformed; D003545:Cysteine / Q000235:genetics; D004220:Disulfides / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D006825:Hybridomas; D016056:Immunodominant Epitopes / Q000276:immunology / Q000378:metabolism*; D007074:Immunoglobulin G / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007145:Immunoglobulin kappa-Chains / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000502:physiology; D050862:Oxidoreductases Acting on Sulfur Group Donors; D017510:Protein Folding; D019163:Reducing Agents / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004220:Disulfides; D016056:Immunodominant Epitopes; D007074:Immunoglobulin G; D007145:Immunoglobulin kappa-Chains; D019163:Reducing Agents; D010088:Oxidoreductases; C056859:IFI30 protein, human; C483811:Ifi30 protein, mouse; D050862:Oxidoreductases Acting on Sulfur Group Donors; D003545:Cysteine