Identification of novel immune adjuvants and their acting mechanism on dendritic cell function

树突状细胞（dc）通过识别多种微生物衍生的分子成分（即免疫佐剂）和产生各种细胞因子，在宿主防御中发挥着重要作用。一组跨膜蛋白toll样受体（TLRs）对这些过程至关重要。我已经通过使用几个基因靶向小鼠阐明了其中的一些机制。我已经鉴定出抗病毒试剂、咪唑喹啉衍生物作为TLR7配体，也揭示了病毒衍生的单链rna也可以作为TLR7配体。TLR3和TLR4分别可以识别双链rna和脂多糖（LPS），它们的信号传导可以诱导I型干扰素（ifn）的产生。发现IKK家族成员IKKε/ι和TBK1对tlr3 /4诱导的I型IFN产生至关重要。这些IKKs也参与了病毒诱导的I型IFN的产生。DC子集浆细胞样DC在tlr中只表达TLR7和TLR9。由于TLR9参与了CpG DNA的识别，因此可以认为PDC可视为核酸识别DC。值得注意的是，PDC在响应TLR7/9信号产生I型IFN，尤其是IFN-α方面是独一无二的。另一个IKK家族成员IKKα被发现对tlr7 /9诱导的PDC产生I型IFN至关重要。此外，利用多种dc，检测了蠕虫提取物诱导il -12的活性。该活性依赖于细胞质TLR适配器MyD88，表明提取物含有一些TLR配体。这些发现将有助于建立新的免疫调节药物。

Dendritic cells (DCs) are critically involved in host defense by recognizing a variety of microorganism-derived molecular components, i.e. immune adjuvants, and producing various cytokines. A group of transmembrane proteins, Toll-like receptors (TLRs), are critical for these processes. I have clarified some of these mechanisms by utilizing several gene targeting mice. I have already identified antiviral reagents, imidazoquinoline derivatives, as TLR7 ligands and also revealed that virus-derived single stranded RNAs can also function as TLR7 ligands. TLR3 and TLR4 can recognize double stranded RNAs and lipopolysaccarides (LPS), respectively, and their signaling can induce type I interferons (IFNs). IκB kinase (IKK) family members, IKKε/ι and TBK1, were found to be critical for TLR3/4-induced type I IFN production. These IKKs were also involved in virus-induced type I IFN production. A DC subset, plasmacytoid DC, expresses TLR7 and TLR9 exclusively among TLRs. Because TLR9 is involved in recognizing CpG DNA, it can be assumed that PDC can be regarded as nucleic acid-recognizing DC. Notably, PDC is unique in producing type I IFN, especially IFN-α, in response to TLR7/9 signaling. Another IKK family member, IKKα, was found to be critical for TLR7/9-induced type I IFN production from PDC. Furthermore, by utilizing a variety of DCs, IL-12-inducing activity was detected in helminth extracts. The activity was dependent on a cytoplasmic TLR adapter, MyD88, indicating that the extracts include some TLR ligands. These findings should contribute to the establishment of novel drugs for immune regulation.