Type I IFN-mediated reversal of TLR tolerance in antigen presenting cells (61.13)

Abstract

Abstract Many synthetic ligands for TLRs, especially TLR 7/8 and 9 agonists, induce potent innate and adaptive immune responses and are thus under consideration as vaccine adjuvants and as anti-cancer agents. In addition, TLR7 and 9 agonists are potent type I IFN inducers and play critical roles in defense against viral infections. Many TLR-mediated responses in antigen presenting cells are also modulated by Type I IFN receptor signals. However, the precise molecular mechanisms involved in cooperation between these two receptors are not clear. We have previously shown that repeated stimulation through TLR7 can induce a state of hyporesponsiveness (TLR tolerance) in B cells characterized by severe defects in major signaling pathways. In this study, we investigated whether simultaneous signals through type I IFN receptor can reverse tolerance in B cells and dendritic cells. We found that signals through type I IFN receptor can prevent and reverse TLR tolerance in mouse and human B cells and in mouse bone marrow derived dendritic cells. The reversal of hyporesponsiveness was associated with activation of p38 and ERK1, 2 and c-Jun phosphorylation. Moreover, Type I IFNR-mediated reversal of tolerance was dependent on the PI3K/Akt/mTOR pathway. A better understanding of how these important signaling pathways interact can significantly increase our ability to develop better vaccine adjuvants and immunotherapeutic agents against cancer.