MTOR Regulates TLR-induced TH1 Responses By C-Fos

Despite IL-12 plays a critical role in priming Th1 and CTL responses, TLR signaling only induces low amounts of IL-12 in DCs and macrophages, implying the existence of stringent regulatory mechanisms. In this study, we sought to uncover the mechanism underlying TLR-induced IL-12 expression and Th1 responses. By systemic screening, we identified a number of protein kinases involved in the regulation of TLR-induced IL-12 expression. In particular, PI3 K, ERK and mTOR play a critical role in the regulation of TLR-induced Th1 responses by regulating IL-12 and IL-10 production in innate immune cells. Moreover, we identified c-Fos as a key molecule mediating mTOR-regulated IL-12 and IL-10 expression in TLR signaling. Mechanistically, mTOR plays a crucial role in c-Fos expression, thereby modulating NF-кB binding to promoters of IL-12 and IL-10. By controlling the expression of a special innate gene program, mTOR can be specifically involved in the regulation of TLR-induced T cell responses. Moreover, blockade of mTOR by Rapamycin significantly improved HBV and HCV vaccine efficacy. Taken together, these results identify a novel mechanism by which mTOR regulates TLR-induced IL-12 and IL-10 production, and provide a new strategy to improve vaccine efficacy.