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*
Department of Microbiology and Immunology, Indiana University School of Medicine and Walther Cancer Institute, Indianapolis, IN 46202; and
Department of Autoimmune Disease Research, Merck Research Laboratories, Rahway, NJ 07065
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 
peptide:class II complexes from these cells
indicated that nearly 20-fold more of an immunodominant epitope derived
from 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 epitope as shown using
Ig-primed DR4 transgenic mice. The bias in epitope presentation was
not linked to differences in class II: 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 epitope; Ag refolding restored 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.
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