title: Tapasin modification on the intracellular epitope HBcAg18-27 enhances HBV-specific CTL immune response and inhibits hepatitis B virus replication in vivo.
abstract: HBV-specific cytotoxic T-lymphocyte (CTL) activity has a very important role in hepatitis B virus clearance. Present studies suggest that Tapasin, a endoplasmic reticulum (ER) chaperone, stabilizes the peptide-receptive MHC I conformation, allowing peptide exchange and increasing more peptides to be translocated into the ER. We have previously testified that cytoplasmic transduction peptide (CTP)-HBcAg(18-27)-Tapasin fusion protein could enter cytoplasm of dendritic cells, and enhance T cells' response to generate specific CTLs efficiently in vitro. In the present study, we evaluated specific immune responses of CTP-HBcAg(18-27)-Tapasin fusion protein in HLA-A2 transgenic mice (H-2K(b)) and anti-viral ability in HBV transgenic mice, and explored the mechanisms probably involved in. The studies showed that CTP-HBcAg(18-27)-Tapasin not only increased production of cytokine IFN-γ and interleukin-2 (IL-2), compared with CTP-HBcAg(18-27), HBcAg(18-27)-Tapasin, and PBS, but also significantly induced the higher percentages of IFN-γ+CD8(+) T cells and specific CTL responses in HLA-A2 transgenic mice. Moreover, enhancement of specific CTL activity induced by the fusion protein reduced HBV DNA and hepatitis B surface antigen (HBsAg) levels and decreased the expression of HBsAg and hepatitis B core antigen (HBcAg) in liver tissue of HBV transgenic mice. In addition, CTP-HBcAg(18-27)-Tapasin could upregulate the expression of JAK2, Tyk2, STAT1, and STAT4 in T lymphocytes in HLA-A2 transgenic mice splenocytes. However, there was no significant difference on the expressions of JAK1, JAK3, and STAT6 between each group. In conclusion, CTP-HBcAg(18-27)-Tapasin fusion protein could enhance not only the percentages of CTLs but also induce robust specific CTL activity and inhibits hepatitis B virus replication in vivo, which was associated with activation of the JAK/STAT signaling pathway.
authors.affiliation: Department of Infectious Disease, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Infectious Disease, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Infectious Disease, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Infectious Disease, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhuo
authors.affiliation: Department of Infectious Disease, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Zhenghao
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Department of Infectious Disease, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Infectious Disease, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Zang
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000276:immunology / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006509:Hepatitis B / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D006512:Hepatitis B Core Antigens / Q000276:immunology*; D007424:Intracellular Fluid / Q000276:immunology / Q000821:virology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D014779:Virus Replication / Q000235:genetics / Q000276:immunology*
chemical_list: D000998:Antiviral Agents; D018984:Epitopes, T-Lymphocyte; D006512:Hepatitis B Core Antigens; D026901:Membrane Transport Proteins; D011993:Recombinant Fusion Proteins; C107762:tapasin