Delivery of Tapasin-modified CTL epitope peptide via cytoplasmic transduction peptide induces CTLs by JAK/STAT signaling pathway in vivo  

作　　者：Shanshan Wu Xiaohua Chen Yuyan Tang Yi Zhang Dan Li Jie Chen Jieling Wang Zhenghao Tang Guoqing Zang Yongsheng Yu Shanshan Wut, Xiaohua Chen, Yuyan Tang, Yi Zhang, Dan Li, Jie Chen, Jieling Wang, Zhenghao Tang, Guoqing Zang, and Yongsheng Yu(Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People＇s Hospital, Shangha 200233, Chin)

机构地区：[1]Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China [2]Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China [3]Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China [4]Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China [5]Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China [6]Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China [7]Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China [8]Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China [9]Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China Correspondence address. Tel: [phone] (Ext. 8673) Fax: [phone] E-mail: [e-mail] (Y.Y.)/[e-mail] (G.Z.) [10]Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China Correspondence address. Tel: [phone] (Ext. 8673) Fax: [phone] E-mail: [e-mail] (Y.Y.)/[e-mail] (G.Z.)

出　　处：《Acta Biochimica et Biophysica Sinica》2018年第2期181-190,共10页生物化学与生物物理学报（英文版）

摘　　要：Hepatitis B virus （HBV）-specific cytotoxic T lymphocytes （CTLs） play a vital role in viral control and clearance. Recent studies have elucidated that Tapasin, an endoplasmic reticulum chaperone, is a well-known molecule that appears to be essential in peptide-loading process. The Janus kinase/sig- nal transducers and activators of transcription （JAK/STAT） pathway plays an important role in immune response regulation and cytokines secretion. We have previously verified that fusion pro- tein CTP-HBcAgls_27-Tapasin could facilitate the maturation of bone marrow derived dendritic cells and enhance specific CTLs responses in vitro, which might be associated with the activation of JAK/STAT signaling pathway. To further explore whether JAK/STAT signaling pathway participated in specific immune responses mediated by CTP-HBcAg18_27-Tapasin, we suppressed the JAK/STAT pathway with pharmacological inhibitor （AG490） in vivo. Our studies showed that the number of IFN-y＋-CD8＋ T cells was decreased significantly compared with other groups after being blocked by AG490. The percentage of IFN-y＋-CD4＋ T cells and IL-2-CD4＋ T ceils was also decreased. Moreover, lower expression levels of Jak2, Tyk2, STAT1, and STAT4 were detected in AG490 group. In add- ition, the secretion levels of Thl-like cytokines were decreased and a weaker specific T-cell response was observed in AG490 group. Furthermore, the levels of HBV DNA and HBsAg in serum and expression levels of HBsAg and HBcAg in liver tissues were elevated after this pathway was inhibited in HBV transgenic mice. These results demonstrate that the JAK/STAT signaling pathway participates in Thl-oriented immune response induced by CTP-HBcAgls_2TTapasin and this might provide a theoretical basis for HBV immunotherapy.Hepatitis B virus （HBV）-specific cytotoxic T lymphocytes （CTLs） play a vital role in viral control and clearance. Recent studies have elucidated that Tapasin, an endoplasmic reticulum chaperone, is a well-known molecule that appears to be essential in peptide-loading process. The Janus kinase/sig- nal transducers and activators of transcription （JAK/STAT） pathway plays an important role in immune response regulation and cytokines secretion. We have previously verified that fusion pro- tein CTP-HBcAgls_27-Tapasin could facilitate the maturation of bone marrow derived dendritic cells and enhance specific CTLs responses in vitro, which might be associated with the activation of JAK/STAT signaling pathway. To further explore whether JAK/STAT signaling pathway participated in specific immune responses mediated by CTP-HBcAg18_27-Tapasin, we suppressed the JAK/STAT pathway with pharmacological inhibitor （AG490） in vivo. Our studies showed that the number of IFN-y＋-CD8＋ T cells was decreased significantly compared with other groups after being blocked by AG490. The percentage of IFN-y＋-CD4＋ T cells and IL-2-CD4＋ T ceils was also decreased. Moreover, lower expression levels of Jak2, Tyk2, STAT1, and STAT4 were detected in AG490 group. In add- ition, the secretion levels of Thl-like cytokines were decreased and a weaker specific T-cell response was observed in AG490 group. Furthermore, the levels of HBV DNA and HBsAg in serum and expression levels of HBsAg and HBcAg in liver tissues were elevated after this pathway was inhibited in HBV transgenic mice. These results demonstrate that the JAK/STAT signaling pathway participates in Thl-oriented immune response induced by CTP-HBcAgls_2TTapasin and this might provide a theoretical basis for HBV immunotherapy.

关 键 词：chaperone Tapasin hepatitis B virus （HBV） T-celt differentiation JAK/STAT signaling pathway virus immunotherapy 

分 类 号：S858.31[农业科学—临床兽医学] TP334.7[农业科学—兽医学]