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Endoplasmic Reticulum Aminopeptidase Associated with Antigen Processing Regulates Quality of Processed Peptides Presented by MHC Class I Molecules¹

Division of Immunology, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720

Effective immune surveillance by CD8 T cells depends on the presentation of diverse peptides by MHC class I (pMHC I) molecules on the cell surface. The pMHC I repertoire is shaped in the endoplasmic reticulum (ER) by the ER aminopeptidase associated with Ag processing (ERAAP). The ERAAP activity is required for producing peptides of appropriate length for generating optimal pMHC I. Paradoxically, ERAAP also inhibits generation of certain peptides such as the SVL9 (SSVVGVWYL) peptide encoded by the H13^a histocompatibility gene and presented by D^b MHC by an unknown mechanism. In this study, we show that the presentation of the SVL9-D^b complex is inhibited when other peptides compete for binding D^b. Conversely, improving the binding of SVL9 peptide to D^b suppresses the inhibition. Interestingly, the inhibitory effect of competitor peptides is observed only when ERAAP is expressed in the same cells. Thus, ERAAP, in concert with MHC I molecules, regulates the quality of processed peptides presented on the cell surface.

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¹ This work was supported by grants from the National Institutes of Health (to N.S.). T.K. is a research fellow of the Japan Society for the Promotion of Science.

² Address correspondence and reprint requests to Dr. Nilabh Shastri, Division of Immunology, LSA 421, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200. E-mail address: nshastri{at}berkeley.edu

³ Abbreviations used in this paper: pMHC I, peptide presented by MHC class I; ER, endoplasmic reticulum; ERAAP, ER aminopeptidase associated with Ag processing; RP, reversed phase; BfA, Brefeldin A; ES, ER-translocation signal.