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Following antigenic challenge, MHC-restricted T cell responses are directed against a few dominant antigenic epitopes. Here, evidence is provided demonstrating the importance of APC in modulating the hierarchy of MHC class II-restricted T cell responses. Biochemical analysis of class II:peptide complexes in B cells revealed the presentation of a hierarchy of peptides derived from the Ig self Ag. Functional studies of kappa peptide:class II complexes from these cells indicated that nearly 20-fold more of an immunodominant epitope derived from kappa L chains was bound to class II DR4 compared with a subdominant epitope from this same Ag. In vivo, T cell responses were preferentially directed against the dominant kappa epitope as shown using Ig-primed DR4 transgenic mice. The bias in kappa epitope presentation was not linked to differences in class II:kappa peptide-binding affinity or epitope editing by HLA-DM. Rather, changes in native Ag structure were found to disrupt presentation of the immunodominant but not the subdominant kappa epitope; Ag refolding restored kappa epitope presentation. Thus, Ag tertiary conformation along with processing reactions within APC contribute to the selective presentation of a hierarchy of epitopes by MHC class II molecules.

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

12/1999

Volume

163

Pages

6413 - 6423

Addresses

Department of Microbiology and Immunology, Indiana University School of Medicine and Walther Cancer Institute, Indianapolis 46202, USA.

Keywords

Antigen-Presenting Cells, T-Lymphocytes, Cell Line, Animals, Mice, Inbred C57BL, Humans, Mice, Peptides, Immunoglobulins, Immunoglobulin G, Histocompatibility Antigens Class II, HLA Antigens, Epitopes, T-Lymphocyte, Immunodominant Epitopes, Immunization, Passive, Antigen Presentation, Amino Acid Sequence, Protein Structure, Tertiary, Protein Binding, Molecular Sequence Data, Immunoglobulin kappa-Chains