| Budget Amount *help |
¥4,020,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Dendritic cells (DCs) recognize a variety of nucleic acids through Toll-like receptors (TLRs) and produce proinflammatory cytokines or type I interferons (IFNs). In this study, we have analyzed the underlying molecular mechanisms on these DC functions. Among TLRs, TLR3, TLR7 and TLR9 are involved in nucleic acid recognition. One DC subset, plasmacytoid DC (pDC), expresses TLR7 and TLR9 exclusively among TLRs and produce a large amount of type I IFNs upon TLR7/9 stimulation. A serine threonine kinase, IkB kinase α (IKKα), is critically involved in type I IFN production from TLR7/9-stimulated pDC. IKKα functioned. through the association with and phosphorylation of a transcription factor, IRF-7, which was known to be critical for type I IFN production by TLR7/9 stimuli. We have further investigated the mechanism by which a double-stranded RNA, poly (A: U) activate DCs. Poly (I: C) is a well-known double-stranded RNA, which can activate DCs through TLR3 and a cytosolic sensor, RIG-Hike receptor (RLR), but it remained unknown how poly (A: U) activates DCs. Poly (A: U) activated pDC to produce type I IFN and IL-12p40 in a TLR7-dependent manner. Poly (A: U) also induced IL-12p40 from conventional DC (cDC) through TLR3 and TLR7. When injected with antigen (Ag) into mice, poly (A: U) could induce clonal expansion of and IFN-y production from Ag-specific CD8-positive T cells. TLR3 was mainly involved in these in vivo effects of poly (A: U). Thus, poly (A: U) can function as an immune adjuvant through TLR3 and TLR7.
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