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 κ. HLA-DR4+ B cells preferentially present an immunodominant IgG-derived epitope, κI, relative to a subdominant κII peptide. κI 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 κ 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 κI epitope from both native and variant IgG was dependent upon cellular expression of IFN-γ-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.