title: Adenovirus Vector Harboring the HBcAg and Tripeptidyl Peptidase II Genes Induces Potent Cellular Immune Responses In Vivo.
abstract: BACKGROUND
  Chronic hepatitis B virus (HBV) infection is associated with a weak but specific cellular immune response of the host to HBV. Tripeptidyl peptidaseⅡ (TPPⅡ), an intracellular macromolecule and proteolytic enzyme, plays an important complementary and compensatory role for the proteasome during viral protein degradation and major histocompatibility complex class I antigen presentation by inducing a specific cellular immune response in vivo. Based on a previous study, we aimed to explore the role of MHC class I antigen presentation in vivo and the mechanisms that may be involved.
  
  
  METHODS
  In this study, recombinant adenoviral vectors harboring the hepatitis B core antigen (HBcAg) and the TPPII gene were constructed (Adv-HBcAg and Adv-HBcAg-TPPII), and H-2Kd HBV-transgenic BALB/c mice and HLA-A2 C57BL/6 mice were immunized with these vectors, respectively. We evaluated the specific immune responses induced by Adv-HBcAg-TPPII in the HBV transgenic BALB/c mice and HLA-A2 C57BL/6 mice as well as the anti-viral ability of HBV transgenic mice, and we explored the underlying mechanisms.
  
  
  RESULTS
  We found that immunization with Adv-HBcAg-TPPII induced the secretion of the cytokines interleukin-2 (IL-2), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) as well as the activities of IFN-γ-secreting CD8+ T cells and CD4+ T cells. In addition, HBcAg-specific CTL activity in C57/BL mice and HBV transgenic animals was significantly enhanced in the Adv-HBcAg-TPPII group. Furthermore, Adv-HBcAg-TPPII decreased the hepatitis B surface antigen (HBsAg) and HBV DNA levels and the amount of HBsAg and HBcAg in liver tissues. Moreover, Adv-HBcAg-TPPII enhanced the expression of T-box transcription factor (T-bet) and downregulated GATA-binding protein 3 (GATA-3) while increasing the expression levels of JAK2, STAT1, STAT4 and Tyk2.
  
  
  CONCLUSIONS
  These results suggested that the JAK/STAT signaling pathway participates in the CTL response that is mediated by the adenoviral vector encoding TPPII. Adv-HBcAg-TPPII could therefore break immune tolerance and stimulate HBV-specific cytotoxic T lymphocyte activity and could have a good therapeutic effect in transgenic mice.
authors.forename: Quanhui
authors.initials: Q
authors.lastname: Tan
authors.forename: Siyuan
authors.initials: S
authors.lastname: Ma
authors.forename: Jianjun
authors.initials: J
authors.lastname: Hu
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Chen
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Yu
authors.forename: Zhenghao
authors.initials: Z
authors.lastname: Tang
authors.forename: Guoqin
authors.initials: G
authors.lastname: Zang
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000410:Alanine Transaminase / Q000097:blood; D000626:Aminopeptidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004279:DNA, Viral / Q000097:blood; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism*; D006512:Hepatitis B Core Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006514:Hepatitis B Surface Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000235:genetics; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000378:metabolism; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D004279:DNA, Viral; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; C494080:Stat1 protein, mouse; C494091:Stat4 protein, mouse; D007371:Interferon-gamma; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D012697:Serine Endopeptidases
keywords: GATA-3; JAK/STAT signaling pathway; MHC class I; T-bet; Tripeptidyl peptidaseⅡ