|Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
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.