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

本课题研究了树突状细胞（DCs）在抗微生物先天免疫和适应性免疫中的作用。在微生物感染时，DC在微生物抗原向T细胞的抗原呈递中起重要作用。同时，通过Toll样受体（TLR）刺激的DC产生各种细胞因子，如白细胞介素-12（IL-12），其对于先天免疫的激活和Thl诱导至关重要。因此，DC在先天性和适应性免疫中起关键作用。DC衍生的IL-12进一步诱导来自NK细胞和DC的干扰素γ（IFN-γ）。我们发现DC衍生的IFN-γ在体内对细胞内病原体单核细胞增生李斯特菌的先天免疫应答中起重要作用。此外，我们证明了DC衍生的IL-15对于诱导炎症反应至关重要。Thl免疫的发生部分地受遗传背景调节。我们检查了携带遗传因子的细胞类型，以通过采用大型利什曼原虫感染来确定Th 1/Th 2应答的发生，并发现DC决定Th 1/Th 2应答的结果。我们还研究了DC中的信号转导途径，发现缺乏磷脂酰肌醇3-激酶（PI 3 K）导致DC产生IL-12的增强。相反，Pten（一种催化与PI 3 K相反的反应的磷酸酶）的缺乏导致DC的IL-12表达减少，表明PI 3 K在IL-12产生的调节中起重要作用。我们进一步证明，缺乏PI 3 K导致Th 1应答增强和Th 2应答降低。Major和委内瑞拉圆线虫感染模型。我们的研究结果表明，PI 3 K在体内决定Th 1/Th 2反应中起关键作用。

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.