The regulation of innate immune responses by dendritic cells through the interaction with microbes

点击翻译按钮获取中文摘要

We studied in this program project the role of dendritic cells (DCs) in innate and adaptive immunity against microbes. Upon microbial infection, DCs play an important role in antigen presentation of microbial antigens to T cells. At the same time, DCs stimulated through Toll-like receptor (TLR) produce various cytokines such as interleukin-12 (IL-12) that is crucial for the activation of innate immunity and Thl induction. DCs thus play critical roles in both innate and adaptive immunity. DC-derived IL-12 further induces interferon γ (IFN-γ) from NK cells and DCs. We showed that DC-derived IFN-γ plays an important role in vivo in innate immune response against an intracellular pathogen, Listeria monocytogenes. In addition, we demonstrated that DC-derived IL-15 is critical for the induction of inflammatory responses. The onset of Thl immunity is in part regulated by genetic background. We examined cell types that carry a genetic factor(s) to determine the onset of Thl/Th2 responses by employing Leishmania major infection and found that DCs determine the outcome of Thl/Th2 responses. We also studied signal transduction pathways in DCs and found that the lack of phosphoinositide 3-kinase (PI3K) results in the enhanced IL-12 production by DCs. In contrast, the lack of Pten, a phosphatase that catalyzes a reaction opposite to PI3K, lead to reduced IL-12 expression by DCs, indicating that PI3K plays an important role in the regulation of IL-12 production. We further demonstrated that the lack of PI3K results in an enhanced Th1 response and reduced Th2 response in vivo using L. major and Strongyloides venezuelensis infection model, respectively. Our results show that PI3K play a critical role in determining Thl/Th2 responses in vivo.