Abstract
Abstract Development of better adjuvant is urgently needed for vaccines whose efficacy depends on potent Th1 response. While TLR ligands represent the most promising adjuvants for Th1 response, induction of only suboptimal IL-12 but evident IL-10 in DCs may limit their efficacy. In this study, we attempted to test the notion that maximizing TLR-induced IL-12 versus IL-10 ratio in innate immune system can be a viable approach to elicit robust Th1 response for vaccine. Systemic screening identified a dozen of small molecule compounds capable of elevating LPS-induced IL-12p70 production in DCs. Interestingly, blocking mTOR directly by Rapamycin, or indirectly by compounds targeting mTOR’s upstream regulator PI3K or ERK, respectively, was able to consistently increase IL-12 but decrease IL-10 induction in LPS-stimulated DCs and macrophages. Our study further demonstrated that blocking mTOR in the innate immune system by a variety of compounds can effectively improve MPL-induced Th1 and antibody responses for HBV vaccine. Moreover, we identified a subset of transcriptional factors whose expression in innate immune cells depends on mTOR activation, whereby revealing novel mechanisms by which mTOR regulates TLR-induced IL-12 and IL-10 expression. In summary, our results suggest that maximizing IL-12 vs IL-10 ratio in innate immune system by blocking mTOR can be a novel approach to boost TLR-induced T cell response for vaccine.
Published Version
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