mTOR regulates TLR-induced c-fos and Th1 responses to HBV and HCV vaccines
mTOR regulates TLR-induced c-fos and Th1 responses to HBV and HCV vaccines
复制标题
mTOR 调节 TLR 诱导的 c-fos 和 Th1 对 HBV 和 HCV 疫苗的反应
DOI：
10.1007/s12250-015-3606-3
复制
发表时间：
2015-06-01
影响因子：
5.5
通讯作者：
Xiao, Hui
中科院分区：
文献类型：
--
作者：
He, Li;Zang, Aiping;Xiao, Hui
尽管IL-12在启动Th1和细胞毒性T淋巴细胞（CTL）反应中起着关键作用，但toll样受体（TLR）信号传导仅在树突状细胞和巨噬细胞中诱导低量的IL-12，这表明存在严格的调节机制。在这项研究中，我们试图揭示tlr诱导IL-12表达和Th1反应的机制。通过系统筛选，我们发现了一些参与tlr诱导的IL-12表达调控的蛋白激酶。特别是，PI3K、ERK和mTOR通过调节先天免疫细胞中IL-12和IL-10的产生，在tlr诱导的Th1应答中发挥关键作用。此外，我们发现c-fos是介导mtor调控的TLR信号中IL-12和IL-10表达的关键分子。从机制上讲，mTOR在c-fos表达中起关键作用，从而调节NFκB与IL-12和IL-10启动子的结合。mTOR通过控制一种特殊先天基因程序的表达，在体内特异性调节tlr诱导的T细胞应答。此外，雷帕霉素阻断mTOR有效地增强了tlr诱导的抗原特异性T细胞和B细胞对HBV和HCV疫苗的反应。综上所述，这些结果揭示了mTOR调控tlr诱导的IL-12和IL-10产生的新机制，为提高疫苗疗效的策略提供了新的见解。
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 responsein 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.