Takahiro Sugiyama

Yokohama City University, Yokohama-shi, Kanagawa-ken, Japan

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Publications (8)64.95 Total impact

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    ABSTRACT: Plasmacytoid dendritic cell (pDC), originating from hematopoietic progenitor cells in the bone marrow (BM), is a unique dendritic cell subset that can produce large amounts of type I interferons (IFNs) by signaling through nucleic acid sensing Toll-like receptors (TLRs), TLR7 or TLR9 (TLR7/9). The molecular mechanisms for pDC function and development remain largely unknown. We have focused on an Ets family transcription factor, Spi-B, highly expressed in pDC. Spi-B could transactivate the type I IFN promoters in synergy with IFN regulatory factor (IRF)-7, which is an essential transcription factor for TLR7/9-induced type I IFN production in pDC. Spi-B-deficient pDC and mice showed defects in TLR7/9-induced type I IFN production. Furthermore, in Spi-B-deficient mice, BM pDC was decreased and showed attenuated expression of a set of pDC-specific genes. Meanwhile, peripheral pDC was increased and this uneven distribution was likely due to defective retainment of mature nondividing pDC in the BM. Expression pattern of cell surface molecules in Spi-B-deficient mice indicated the involvement of Spi-B in pDC development. The developmental defects of pDC in Spi-B-deficient mice were more prominent in BM than in peripheral lymphoid organs and intrinsic to pDC. Thus, Spi-B plays critical roles in pDC function and development.
    Blood 10/2012; · 9.78 Impact Factor
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    ABSTRACT: Understanding dendritic cell (DC) subset functions should lead to the development of novel types of vaccine. Here we characterized expression of XC chemokine receptor 1 (XCR1) and its ligand, XCL1. Murine XCR1 was the only chemokine receptor selectively expressed in CD8alpha(+) conventional DCs. XCL1 was constitutively expressed in NK cells, which contribute to serum XCL1 levels. NK and CD8(+) T cells increased XCL1 production upon activation. These expression patterns were conserved in human blood cells, including the BDCA3(+) DC subset. Thus, in human and mice, certain DC subsets should be chemotactic towards NK or activated CD8(+) T cells through XCR1.
    Biochemical and Biophysical Research Communications 07/2010; 397(4):756-61. · 2.41 Impact Factor
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    ABSTRACT: A plasmacytoid dendritic cell (DC) can produce large amounts of type I IFNs after sensing nucleic acids through TLR7 and TLR9. IkappaB kinase alpha (IKKalpha) is critically involved in this type I IFN production through its interaction with IFN regulatory factor-7. In response to TLR7/9 signaling, conventional DCs can also produce IFN-beta but not IFN-alpha in a type I IFN-independent manner. In this study, we showed that IKKalpha was required for production of IFN-beta, but not of proinflammatory cytokines, by TLR7/9-stimulated conventional DCs. Importantly, IKKalpha was dispensable for IFN-beta gene upregulation by TLR4 signaling. Biochemical analyses indicated that IKKalpha exerted its effects through its interaction with IFN regulatory factor-1. Furthermore, IKKalpha was involved in TLR9-induced type I IFN-independent IFN-beta production in vivo. Our results show that IKKalpha is a unique molecule involved in TLR7/9-MyD88-dependent type I IFN production through DC subset-specific mechanisms.
    The Journal of Immunology 03/2010; 184(7):3341-5. · 5.52 Impact Factor
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    ABSTRACT: a b s t r a c t Understanding dendritic cell (DC) subset functions should lead to the development of novel types of vac-cine. Here we characterized expression of XC chemokine receptor 1 (XCR1) and its ligand, XCL1. Murine XCR1 was the only chemokine receptor selectively expressed in CD8a + conventional DCs. XCL1 was con-stitutively expressed in NK cells, which contribute to serum XCL1 levels. NK and CD8 + T cells increased XCL1 production upon activation. These expression patterns were conserved in human blood cells, including the BDCA3 + DC subset. Thus, in human and mice, certain DC subsets should be chemotactic towards NK or activated CD8 + T cells through XCR1.
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    ABSTRACT: Double-stranded RNA (dsRNA) is produced upon viral infection and can activate innate immunity. Polyinosinic:polycytidylic acids [poly(I:C)] is a synthetic mimetic of dsRNA and functions through an endosomal receptor, Toll-like receptor (TLR) 3 or cytosolic receptors. Another type of dsRNA, polyadenylic:polyuridylic acids [poly(A:U)], can also act as an immune adjuvant, but it remains unclear how it exhibits its adjuvant effects. Here, we have characterized the adjuvant effects of poly(A:U). Poly(A:U) could induce both IFN-alpha and IL-12p40 from murine bone marrow dendritic cells (DCs). Poly(A:U)-induced IFN-alpha production depended on a DC subset, plasmacytoid dendritic cell (pDC), and required TLR7. IL-12p40 was also produced by poly(A:U)-stimulated pDC in a TLR7-dependent manner. In addition to pDC, conventional dendritic cell (cDC) also produced IL-12p40 in response to poly(A:U). This IL-12p40 induction resulted from two cDC subsets, CD24(high) cDC and CD11b(high) cDC in a TLR3- and TLR7-dependent manner, respectively. In vivo injection of poly(A:U) with antigen led to clonal expansion of and IFN-gamma production from antigen-specific CD8(+) T cells. Consistent with the in vitro findings, TLR3 and TLR7 were required for the clonal T-cell expansion. Notably, TLR3, rather than TLR7, was critical for generating IFN-gamma-producing CD8(+) T cells. CD8(+) T-cell responses induced by poly(A:U) were independent of type I IFN signaling. Our results demonstrate that poly(A:U) functions as an in vivo immunoadjuvant mainly through TLR3 and TLR7.
    International Immunology 02/2008; 20(1):1-9. · 3.14 Impact Factor
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    ABSTRACT: The Toll-like receptor (TLR) family has important roles in microbial recognition and dendritic cell activation. TLRs 7 and 9 can recognize nucleic acids and trigger signalling cascades that activate plasmacytoid dendritic cells to produce interferon-alpha (IFN-alpha) (refs 7, 8). TLR7/9-mediated dendritic cell activation is critical for antiviral immunity but also contributes to the pathogenesis of systemic lupus erythematosus, a disease in which serum IFN-alpha levels are elevated owing to plasmacytoid dendritic cell activation. TLR7/9-induced IFN-alpha induction depends on a molecular complex that contains a TLR adaptor, MyD88, and IFN regulatory factor 7 (IRF-7) (refs 10-14), but the underlying molecular mechanisms are as yet unknown. Here we show that IkappaB kinase-alpha (IKK-alpha) is critically involved in TLR7/9-induced IFN-alpha production. TLR7/9-induced IFN-alpha production was severely impaired in IKK-alpha-deficient plasmacytoid dendritic cells, whereas inflammatory cytokine induction was decreased but still occurred. Kinase-deficient IKK-alpha inhibited the ability of MyD88 to activate the Ifna promoter in synergy with IRF-7. Furthermore, IKK-alpha associated with and phosphorylated IRF-7. Our results identify a role for IKK-alpha in TLR7/9 signalling, and highlight IKK-alpha as a potential target for manipulating TLR-induced IFN-alpha production.
    Nature 05/2006; 440(7086):949-53. · 38.60 Impact Factor
  • Takahiro Sugiyama, Tsuneyasu Kaisho
    Nippon rinsho. Japanese journal of clinical medicine 05/2005; 63 Suppl 4:97-101.
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    ABSTRACT: Synthetic immunostimulatory nucleic acids such as CpG DNA are being harnessed therapeutically as vaccine adjuvants, anticancer or antiallergic agents. Efforts to identify nucleic acid-based agents capable of more specifically modulating the immune system are being developed. The current study identifies a novel class of single-stranded oligoribonucleotides (ORN) containing unmethylated CpG motifs and a poly(G) run at the 3' end (CpG ORN) that directly stimulate human CD14+CD11c+ monocytes but not dendritic cells or B cells. CpG ORN activate NF-kappaB and p38 MAPK, resulting in IL-6 and IL-12 production and costimulatory molecule up-regulation but not IFNalpha. Methylation of cytosine at the 5' portion in core CpG motif abrogates such activation. TLR3, 7, 8, or 9 alone did not confer response to CpG ORN, in contrast to previously reported respective nucleic acid ligands. These data suggest that CpG ORN represent a novel class of synthetic immunostimulatory nucleic acids with distinct target cells, receptors, and functions from that of previously known immunomodulatory nucleic acids.
    The Journal of Immunology 03/2005; 174(4):2273-9. · 5.52 Impact Factor