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TAP-Independent Presentation of CTL Epitopes by Trojan Antigens¹

Jun Lu^*, Peter J. Wettstein^*, Yuichiro Higashimoto, Ettore Appella and Esteban Celis^2,*

^* Department of Immunology and Cancer Center, Mayo Clinic and Mayo Graduate School, Rochester, MN 55905; and Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

The majority of CTL epitopes are derived from intracellular proteins that are degraded in the cytoplasm by proteasomes into peptides that are transported into the endoplasmic reticulum by the TAP complex. These peptides can be further processed into the optimal size (8–10 residues) for binding with nascent MHC class I molecules, generating complexes that are exported to the cell surface. Proteins or peptides containing CTL epitopes can be introduced into the cytoplasm of APCs by linking them to membrane-translocating Trojan carriers allowing their incorporation into the MHC class I Ag-processing pathway. The present findings suggest that these "Trojan" Ags can be transported into the endoplasmic reticulum in a TAP-independent way where they are processed and trimmed into CTL epitopes. Furthermore, processing of Trojan Ags can also occur in the trans-Golgi compartment, with the participation of the endopeptidase furin and possibly with the additional participation of a carboxypeptidase. We believe that these findings will be of value for the design of CTL-inducing vaccines for the treatment or prevention of infectious and malignant diseases.

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