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In APCs, the Autologous Peptides Selected by the Diabetogenic I-A^g7 Molecule Are Unique and Determined by the Amino Acid Changes in the P9 Pocket¹

Anish Suri^*, Ilan Vidavsky, Koen van der Drift, Osami Kanagawa^*, Michael L. Gross and Emil R. Unanue^2,*

^* Department of Pathology and Immunology, and Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110; and Department of Chemistry, Washington University, St. Louis, MO 63130

We demonstrate in this study the great degree of specificity in peptides selected by a class II MHC molecule during processing. In this specific case of the diabetogenic I-A^g7 molecule, the P9 pocket of I-A^g7 plays a critical role in determining the final outcome of epitope selection, a conclusion that is important in interpreting the role of this molecule in autoimmunity. Specifically, we examined the display of naturally processed peptides from APCs expressing either I-A^g7 molecules or a mutant I-A^g7 molecule in which the 57Ser residue was changed to an Asp residue. Using mass spectrometry analysis, we identified over 50 naturally processed peptides selected by I-A^g7-expressing APCs. Many peptides were selected as families with a core sequence and variable flanks. Peptides selected by I-A^g7 were unusually rich in the presence of acidic residues toward their C termini. Many peptides contained short sequences of two to three acidic residues. In binding analysis, we determined the core sequences of many peptides and the interaction of the acidic residues with the P9 pocket. However, different sets of peptides were isolated from APCs bearing a modified I-A^g7 molecule. These peptides did not favor acidic residues toward the carboxyl terminus.

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