Enhancing major histocompatibility complex class I antigen presentation by targeting antigen to centrosomes.
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 gamma-tubulin, an established centrosomal marker, with a model tumor antigen, human papillomavirus type 16 (HPV-16) E7, in a DNA vaccine. The linkage of gamma-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 gamma-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.
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
Chien-Fu
CF
Hung
Wen-Fang
WF
Cheng
Liangmei
L
He
Morris
M
Ling
Jeremy
J
Juang
Cheng-Tao
CT
Lin
T-C
TC
Wu
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D018385:Centrosome / Q000276:immunology* / Q000378:metabolism; D020740:Chimerin Proteins / Q000235:genetics / Q000276:immunology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D008175:Lung Neoplasms / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050725:Papillomavirus E7 Proteins; D014162:Transfection; D014404:Tubulin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D019496:Cancer Vaccines; D020740:Chimerin Proteins; D015395:Histocompatibility Antigens Class I; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C073119:TAP1 protein, human; C486171:Tap1 protein, mouse; D014404:Tubulin; D019444:Vaccines, DNA; C059731:oncogene protein E7, Human papillomavirus type 16