mTOR regulates TLR-induced c-fos and Th1 responses to HBV and HCV vaccines

作     者：Li He Aiping Zang Min Du Dapeng Ma Chuanping Yuan Chun Zhou Jing Mu Huanjing Shi Dapeng Li Xulin Huang Qiang Deng Jianhua Xiao Huimin Yan Lijian Hui Ke Lan Sidong Xiong Xiaoxia Li Zhong Huang Hui Xiao 

作者机构：Institute of Biology and Medical Sciences Soochow University Unit of Immune Signaling and Regulation Key Laboratory of Molecular Virology & Immunology Institut Pasteur of Shanghai Chinese Academy of Sciences Unit of Vaccinology and Anti-viral Strategies Key Laboratory of Molecular Virology & Immunology Institut Pasteur of Shanghai Chinese Academy of Sciences Unit of Tumor Virology Key Laboratory of Molecular Virology & Immunology Institut Pasteur of ShanghaiChinese Academy of Sciences Institute of Pathogenic Biology University of South China Mucosal Immunity Research Group State Key Laboratory of Virology Wuhan Institute of Virology Chinese Academy of Sciences State Key Laboratory of Cell Biology Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Department of Immunology Lerner Research Institute Cleveland Clinic Foundation Vaccine Center Institut Pasteur of Shanghai Chinese Academy of Sciences 

出 版 物：《Virologica Sinica》 (中国病毒学（英文版）)

年 卷 期：2015年第30卷第3期

页      面：174-189页

核心收录：

学科分类：0710[理学-生物学] 1007[医学-药学(可授医学、理学学位)] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100401[医学-流行病与卫生统计学] 10[医学] 

基　　金：support by National Natural Science Foundation of China grants 31070779 and 31170862 (to H.X.), 31100623 (to A.Z.) and 31270917 (to M.D.) National Key laboratory of Virology grant (2014IOV006) H.X. is supported by Chinese Academy of Sciences "100-talent" program National program for returned oversea talents the CAS/SAFEA International Partnership Program for Creative Research Teams Shanghai Pasteur foundation 

主　　题：Toll-like receptor(TLR) mTOR vaccine hepatitis B virus(HBV) hepatitis C virus(HCV) adjuvant c-fos 

摘      要：Although IL-12 plays a critical role in priming Th1 and cytotoxic T lymphocyte(CTL) responses, Toll-like receptor(TLR) signaling only induces low amounts of IL-12 in dendritic cells and macrophages, implying the existence of stringent regulatory mechanisms. In this study, we sought to uncover the mechanisms underlying TLR-induced IL-12 expression and the Th1 response. By systemic screening, we identified a number of protein kinases involved in the regulation of TLRinduced IL-12 expression. In particular, PI3 K, ERK, and m TOR play critical roles in the TLR-induced Th1 response by regulating IL-12 and IL-10 production in innate immune cells. Moreover, we identified c-fos as a key molecule that mediates m TOR-regulated IL-12 and IL-10 expression in TLR signaling. Mechanistically, m TOR plays a crucial role in c-fos expression, thereby modulating NFκB binding to promoters of IL-12 and IL-10. By controlling the expression of a special innate gene program, m TOR can specifically regulate the TLR-induced T cell response in vivo. Furthermore, blockade of m TOR by rapamycin efficiently boosted TLR-induced antigen-specific T and B cell responses to HBV and HCV vaccines. Taken together, these results reveal a novel mechanism through which m TOR regulates TLR-induced IL-12 and IL-10 production, contributing new insights for strategies to improve vaccine efficacy.