Role of APC in the selection of immunodominant T cell epitopes

Following antigenic challenge, MHC-restricted T cell responses are directed against a few dominant antigenic epitopes, Here, evidence is provided demo nstrating the importance of APC in modulating the hierarchy of MHC class II -restricted T cell responses. Biochemical analysis of class II:peptide comp lexes in B cells revealed the presentation of a hierarchy of peptides deriv ed from the Ig self Ag, Functional studies of kappa peptide:class II comple xes from these cells indicated that nearly 20-fold more of an immunodominan t epitope derived from kappa L chains was bound to class II DR4 compared wi th a subdominant epitope from this same Ag, In vivo, T cell responses were preferentially directed against the dominant kappa epitope as shown using I g-primed DR4 transgenic mice. The bias in kappa epitope presentation was no t linked to differences in class IZ:kappa peptide-binding affinity or epito pe editing by HLA-DM. Rather, changes in native Ag structure were found to disrupt presentation of the immunodominant but not the subdominant kappa ep itope; Ag refolding restored kappa epitope presentation. Thus, Ag tertiary conformation along with processing reactions within APC contribute to the s elective presentation of a hierarchy of epitopes by MHC class II molecules.