title: mTOR regulates TLR-induced c-fos and Th1 responses to HBV and HCV vaccines.
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.
authors.affiliation: Institute of Biology and Medical Sciences, Soochow University, Soochow, 215123, China.
authors.forename: Li
authors.initials: L
authors.lastname: He
authors.forename: Aiping
authors.initials: A
authors.lastname: Zang
authors.forename: Min
authors.initials: M
authors.lastname: Du
authors.forename: Dapeng
authors.initials: D
authors.lastname: Ma
authors.forename: Chuanping
authors.initials: C
authors.lastname: Yuan
authors.forename: Chun
authors.initials: C
authors.lastname: Zhou
authors.forename: Jing
authors.initials: J
authors.lastname: Mu
authors.forename: Huanjing
authors.initials: H
authors.lastname: Shi
authors.forename: Dapeng
authors.initials: D
authors.lastname: Li
authors.forename: Xulin
authors.initials: X
authors.lastname: Huang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Deng
authors.forename: Jianhua
authors.initials: J
authors.lastname: Xiao
authors.forename: Huimin
authors.initials: H
authors.lastname: Yan
authors.forename: Lijian
authors.initials: L
authors.lastname: Hui
authors.forename: Ke
authors.initials: K
authors.lastname: Lan
authors.forename: Sidong
authors.initials: S
authors.lastname: Xiong
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.forename: Zhong
authors.initials: Z
authors.lastname: Huang
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D016174:Hepacivirus / Q000276:immunology*; D006515:Hepatitis B virus / Q000276:immunology*; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism*; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D051193:Toll-Like Receptors; D014765:Viral Vaccines; D016753:Interleukin-10; D018664:Interleukin-12; D058570:TOR Serine-Threonine Kinases