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Enhancing Major Histocompatibility Complex Class I Antigen Presentation by Targeting Antigen to Centrosomes¹

Departments of Pathology [C-F. H., W-F. C., L. H., M. L., J. J., C-T. L., T-C. W.], Obstetrics and Gynecology [T-C. W.], Molecular Microbiology and Immunology [T-C. W.], and Oncology [T-C. W.], Johns Hopkins Medical Institutions, Baltimore, Maryland 21205; Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan [W-F. C.]; Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei, Taiwan [C-T. L.]

Several strategies that increase proteasomal degradation of antigen have been shown to improve MHC class I presentation of antigen. Because recent studies have demonstrated that the centrosome is a subcellular compartment rich in proteasomes, we hypothesized that targeting a tumor antigen to centrosomal compartments would enhance both the MHC class I presentation of antigen and the vaccine potency. We, therefore, created a chimera of -tubulin, an established centrosomal marker, with a model tumor antigen, human papillomavirus type 16 (HPV-16) E7, in a DNA vaccine. The linkage of -tubulin to E7-targeted antigen to centrosomal compartments, resulted in enhanced MHC class I presentation of E7, and led to a marked increase in the number of E7-specific CD8⁺ T-cell precursors as well as a potent CD4-independent antitumor effect against an E7-expressing tumor cell line, TC-1. In addition, vaccination with -tubulin/E7 DNA in transporter associated with antigen presentation (TAP)-1-knockout mice revealed that the enhancement of E7-specific CD8⁺ T-cell immune responses is TAP-1-dependent. Our data suggest that the centrosome may be an important locus for MHC class I antigen processing and that targeting antigen to the centrosome can improve DNA vaccine potency.

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