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Virologica Sinica, 30 (3) : 174-189, 2015
Research Article
mTOR regulates TLR-induced c-fos and Th1 responses to HBV and HCV vaccines
1. Institute of Biology and Medical Sciences, Soochow University, Soochow 215123, China
2. Unit of Immune Signaling and Regulation, Key Laboratory of Molecular Virology & Immunology, Institut
Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
3. Institute of Pathogenic Biology, University of South China, Hengyang 421001, China
4. Unit of Vaccinology and Anti-viral Strategies, Key Laboratory of Molecular Virology & Immunology, Institut
Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
5. Unit of Tumor Virology, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai,
Chinese Academy of Sciences, Shanghai 200031, China
6. Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese
Academy of Sciences, Wuhan 430071, China
7. State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for
Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
8. Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland 44195,
USA
9. Vaccine Center, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
 Correspondence: huixiao@ips.ac.cn
(1237.71KB)  
Abstract
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, PI3K, ERK, and mTOR 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 mTOR-regulated IL-12 and IL-10 expression in TLR signaling. Mechanistically, mTOR 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, mTOR can specifically regulate the TLR-induced T cell response in vivo. Furthermore, blockade of mTOR 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 mTOR regulates TLR-induced IL-12 and IL-10 production, contributing new insights for strategies to improve vaccine efficacy.
Received: 11 May 2015  Accepted: 21 May 2015  Published online: 11 Jun 2015
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