title: TAT-mediated gp96 transduction to APCs enhances gp96-induced antiviral and antitumor T cell responses.
abstract: The heat shock protein gp96 is an adjuvant that can elicit T cell responses against cancer and infectious diseases, via antigen presentation, in both rodent models and clinical trials. Its uptake and internalization into antigen presenting cells (APCs) is a critical step in gp96-mediated immune responses. This study examined strategies to improve the cell internalization and T cell activation of gp96. It was found that recombinant fusion with the cell-penetrating peptide TAT (trans-activator of transcription) slightly decreased the aggregation level of gp96 and significantly increased its internalization into macrophages. Furthermore, immunization with the TAT-gp96 fusion dramatically enhanced gp96-mediated hepatitis B virus (HBV)-specific T cell responses and its antiviral efficiency in HBV transgenic mice compared to rgp96. In addition, the inclusion of TAT significantly improved the antitumor T cell immune response to a gp96 vaccine in the B16 melanoma model. These results provide evidence that the efficient transduction of gp96 into APCs can significantly enhance the outcome of gp96-based immunotherapy, and therefore provide a basis for more efficient approaches to improving the immunoregulatory and adjuvant functions of this unique T cell adjuvant.
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Bao
authors.initials: B
authors.lastname: Zhao
authors.forename: Yanzhong
authors.initials: Y
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhang
authors.forename: Yaxing
authors.initials: Y
authors.lastname: Xu
authors.forename: Lizhao
authors.initials: L
authors.lastname: Chen
authors.forename: Changfei
authors.initials: C
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Ju
authors.forename: Songdong
authors.initials: S
authors.lastname: Meng
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism*; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D002460:Cell Line; D004705:Endocytosis; D005260:Female; D006515:Hepatitis B virus / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D011993:Recombinant Fusion Proteins; C052646:sarcoma glycoprotein gp96 rejection antigens; D054322:tat Gene Products, Human Immunodeficiency Virus