研究等業績 - その他 - 海老原　敬

MAVS-dependent IRF3/7 bypass of interferon p-induction restricts the response to measles infection in CD150Tg mouse bone marrow-derived dendritic cells

Takaki Hiromi, Honda Kenya, Atarashi Koji, Kobayashi Fukiko, Ebihara Takashi, Oshiumi Hiroyuki, Matsumoto Misako, Shingai Masashi, Seya Tsukasa

Molecular immunology ( Pergamon-elsevier science ltd )  57 ( 2 ) 100 - 109   2014年

Measles virus (MV) infects CD150Tg/ifnar (IFN alpha receptor)(-/-) mice but not CD150 (a human MV receptor)-transgenic (Tg) mice. We have shown that bone marrow-derived dendritic cells (BMDCs) from CD150Tg/Ifnar(-/-) mice are permissive to MV in contrast to those from simple CD150Tg mice, which reveals a crucial role of type I interferon (IFN) in natural tropism against MV. Yet, the mechanism whereby BMDCs produce initial type I IFN has not been elucidated in MV infection. RNA virus infection usually allows cells to generate double-stranded RNA and induce activation of IFN regulatory factor (IRF) 3/7 transcription factors, leading to the production of type I IFN through the retinoic acid-inducible gene I (RIG-I)/melanoma differentiation-associated gene 5 (MDA5)-mitochondrial antiviral signaling protein (MAVS) pathway. In mouse experimental BMDCs models, we found CD150Tg/Mavs(-/-)BMDCs, but not CD150Tg/Irf3(-/-)/Irf7-/-BMDCs, permissive to MV. IFN-alpha/beta were not induced in MV-infected CD150Tg/Mavs--/-BMDCs, while IFN-13 was subtly induced in CD150Tg/Irf3(-/-)/Irf7(-/-)BMDCs. In vivo systemic infection was therefore established by transfer of MV-infected CD150Tg/Mavs-/- BMDCs to CD150Tg//fnar-/- mice. These data indicate that MAVS-dependent, IRF3/7-independent IFN-13 induction triggers the activation of the IFNAR pathway so as to restrict the spread of MV by infected BMDCs. Hence, MAVS participates in the initial induction of type I IFN in BMDCs and IFNAR protects against MV spreading. We also showed the importance of IL-10-producing CD4+ T cells induced by MV-infected BMDCs in vitro, which may account for immune modulation due to the functional aberration of DCs. (C) 2013 Elsevier Ltd. All rights reserved.

DOI

INAMはIFNγ誘導を引き起こす迅速なNKアクセサリー細胞の相互作用に重要な役割を担っている(INAM plays a critical role in rapid NK-accessory cell interaction leading to IFN γ induction)

Kasamatsu Jun, Oshiumi Hiroyuki, Ebihara Takashi, Matsumoto Misako, Seya Tsukasa

日本免疫学会総会・学術集会記録 ( (NPO)日本免疫学会 )  42 ( Proceedings ) 83 - 83   2013年11月

誘導性MHCクラスI発現で明らかとなった、MHCクラスI(MHC-I)とLy49受容体のトランス相互作用を介したNK細胞のライセンシング(教育)(NK cell licensing(education) through Ly49 receptor trans-interactions with MHC class I(MHC-I) as revealed by inducible MHC-I expression)

Ebihara Takashi, Jonsson A. Helena, Yokoyama M. Wayne

日本免疫学会総会・学術集会記録 ( (NPO)日本免疫学会 )  42 ( Proceedings ) 82 - 82   2013年11月

生体内においてIRF-3-dependent NK-activating moleculeはNK細胞の活性化を制御する

笠松純, 押海裕之, 海老原敬, 松本美佐子, 瀬谷司

日本生体防御学会学術総会講演抄録集   24th   2013年

J-GLOBAL

Cross-priming for antitumor ctl induced by soluble ag + polyi: C depends on the ticam-1 pathway in mouse cd11c+/CD8α+ dendritic cells

Azuma, M., Ebihara, T., Oshiumi, H., Matsumoto, M., Seya, T.

OncoImmunology   1 ( 5 )   2012年

DOI

樹状細胞・マクロファージによる免疫応答調節と免疫病態との関連 マウスAg提示細胞においてPolyI:C誘発性交差プライミングと抗腫瘍CTLはTICAM-1経路に依存する(PolyI:C-induced cross-priming and antitumor CTL depends on the TICAM-1 pathway in mouse Ag-presenting cells)

Azuma Masahiro, Ebihara Takashi, Matsumoto Misako, Seya Tsukasa

日本免疫学会総会・学術集会記録 ( (NPO)日本免疫学会 )  40   198 - 198   2011年11月

Pattern recognition receptors of innate immunity and their application to tumor immunotherapy

Tsukasa Seya, Hiroaki Shime, Takashi Ebihara, Hiroyuki Oshiumi, Misako Matsumoto

Cancer Science ( Wiley )  101 ( 2 ) 313 - 320   2010年02月

DOI

Dendritic cell-derived TNF-α is responsible for development of IL-10-producing CD4+ T cells

Hirata Noriyuki, Yanagawa Yoshiki, Satoh Masashi, Ogura Hisako, Ebihara Takashi, Noguchi Masayuki, Matsumoto Machiko, Togashi Hiroko, Seya Tsukasa, Onoé Kazunori, Iwabuchi Kazuya

Cellular Immunology ( Elsevier )  261 ( 1 ) 37 - 41   2010年

Immature dendritic cells (DCs) appear to be involved in peripheral immune tolerance via induction of IL-10-producing CD4+ T cells. We examined the role of TNF-α in generation of the IL-10-producing CD4+ T cells by immature DCs. Immature bone marrow-derived DCs from wild type (WT) or TNF-α^[-/-] mice were cocultured with CD4+ T cells from OVA specific TCR transgenic mice (OT-II) in the presence of OVA_[323-339] peptide. The WT DCs efficiently induced the antigen-specific IL-10-producing CD4+ T cells, while the ability of the TNF-α^[-/-] DCs to induce these CD4+ T cells was considerably depressed. Addition of exogenous TNF-α recovered the impaired ability of the TNF-α^[-/-] DCs to induce IL-10-producing T cells. However, no difference in this ability was observed between TNF-α^[-/-] and WT DCs after their maturation by LPS. Thus, TNF-α appears to be critical for the generation of IL-10-producing CD4+ T cells during the antigen presentation by immature DCs.

DOI

IL-6 and IFN-α from dsRNA-stimulated dendritic cells control expansion of regulatory T cells

Kubota Nobuhiko, Ebihara Takashi, Matsumoto Misako, Gando Satoshi, Seya Tsukasa

Biochemical and Biophysical Research Communications ( Elsevier )  391 ( 3 ) 1421 - 1426   2010年

Foxp3+CD4+ regulatory T cells (Treg) control not only autoinimunity but also the effective immune response against RNA virus infections, which produces virus-derived double-stranded RNA (dsRNA). To induce effective anti-viral immunity, it is a key issue to learn how Treg respond to dsRNA in vitro and in vivo. We here showed that synthetic dsRNA, polyI:C, caused peripheral expansion of functional Treg in a TICAM-1- and IL-6-dependent manner in vivo. PolyI:C did not expand Treg directly, but promoted the expansion of naturally occurring Treg indirectly through IL-6 produced from dendritic cells (DCs). In addition, the expansion of Treg by IL-6 was inhibited by IFN-α from polyI:C-stimulated DCs. These data suggest that the balance of IL-6 and IFN-α in the region of RNA virus infection may determine the number of peripheral Treg, which affects the effective immune responses against viruses.

DOI

The peptide sequence of diacyl lipopeptides determines dendritic cell TLR2-mediated NK activation

Azuma, M., Sawahata, R., Akao, Y., Ebihara, T., Yamazaki, S., Matsumoto, M., Hashimoto, M., Fukase, K., Fujimoto, Y., Seya, T.

PLoS ONE   5 ( 9 )   2010年

Natural killer (NK) cells are lymphocyte effectors that are activated to control certain microbial infections and tumors. Many NK-activating and regulating receptors are involved in regulating NK cell function. In addition, activation of naïve NK cells is fundamentally triggered by cytokines or myeloid dendritic cells (mDC) in various modes. In this study, we synthesized 16 S-[2,3-bis(palmitoyl)propyl]cysteine (Pam2Cys) lipopeptides with sequences designed from lipoproteins of Staphylococcus aureus, and assessed their functional properties using mouse (C57BL/6) bone marrow-derived DC (BMDC) and NK cells. NK cell activation was evaluated by three criteria: IFN-gamma production, up-regulation of NK activation markers and cytokines, and NK target (B16D8 cell) cytotoxicity. The diacylated lipopeptides acted as TLR2 ligands, inducing up-regulation of CD25/CD69/CD86, IL-6, and IL-12p40, which represent maturation of BMDC. Strikingly, the Pam2Cys lipopeptides induced mouse NK cell activation based on these criteria. Cell-cell contact by Pam2Cys peptide-stimulated BMDC and NK cells rather than soluble mediators released by stimulated BMDC induced activation of NK cells. For most lipopeptides, the BMDC TLR2/MyD88 pathway was responsible for driving NK activation, while some slightly induced direct activation of NK cells via the TLR2/MyD88 pathway in NK cells. The potential for NK activation was critically regulated by the peptide primary sequence. Hydrophobic or proline-containing sequences proximal to the N-terminal lipid moiety interfered with the ability of lipopeptides to induce BMDC-mediated NK activation. This mode of NK activation is distinctly different from that induced by polyI:C, which is closely associated with type I IFN-inducing pathways of BMDC. These results imply that the MyD88 pathway of BMDC governs an alternative NK-activating pathway in which the peptide sequence of TLR2-agonistic lipopeptides critically affects the potential for NK activation.

DOI PubMed

樹状細胞における細胞内シグナル伝達とその意義 骨髄由来樹状細胞におけるTLR3/TICAM-1経路を介したクロスプレゼンテーションの制御(Regulation of cross-presentation through the TLR3/TICAM-1 pathway in mDC)

Azuma Masahiro, Ebihara Takashi, Kubota Nobuhiko, Matsumoto Misako, Seya Tsukasa

日本免疫学会総会・学術集会記録 ( (NPO)日本免疫学会 )  39   181 - 181   2009年11月

Dendritic Cell/NK Cell Interaction in RNA Virus Infection

Takashi Ebihara, Misako Matsumoto, Tsukasa Seya

Current Immunology Reviews ( Bentham Science Publishers Ltd. )  5 ( 3 ) 200 - 207   2009年08月

DOI

Enhancement of antitumor natural killer cell activation by orally administered Spirulina extract in mice

Yuusuke Akao, Takashi Ebihara, Hisayo Masuda, Yoshiko Saeki, Takashi Akazawa, Kaoru Hazeki, Osamu Hazeki, Misako Matsumoto, Tsukasa Seya

Cancer Science ( Wiley )  100 ( 8 ) 1494 - 1501   2009年08月

Oral administration of hot-water extract of Spirulina, cyanobacterium Spirulina platensis, leads to augmentation of NK cytotoxicity in humans. Here, we applied to syngeneic tumor-implant mice (C57BL/6 versus B16 melanoma) Spirulina to elucidate the mechanism of raising antitumor NK activation. A B16D8 subcell line barely expressed MHC class I but about 50% expressed Rae-1, a ligand for NK activation receptor NKG2D. The Rae-1-positive population of implant B16 melanoma was effectively eliminated in the tumor mass progressed in mice. This antitumor activity was induced in parallel with IFN-gamma and abolished in mice by treatment with asialoGM-1 but not CD8beta Ab, suggesting the effector is NK cell. NK cell activation occurred in the spleen of wild-type mice medicated with Spirulina. This Spirulina-mediated enhanced NK activation was abrogated in MyD88 -/- mice but not in TICAM-1 -/- mice. The NK activating properties of Spirulina depending on MyD88 were confirmed with in vitro bone marrow-derived dendritic cells expressing TLR2/4. In D16D8 tumor challenge studies, the antitumor effect of Spirulina was abolished in MyD88 -/- mice. Hence, orally administered Spirulina enhances tumoricidal NK activation through the MyD88 pathway. Spirulina exerted a synergistic antitumor activity with BCG-cell wall skeleton, which is known to activate the MyD88 pathway via TLR2/4 with no NK enhancing activity. Spirulina and BCG-cell wall skeleton synergistically augmented IFN-gamma production and antitumor potential in the B16D8 versus C57BL/6 system. We infer from these results that NK activation by Spirulina has some advantage in combinational use with BCG-cell wall skeleton for developing adjuvant-based antitumor immunotherapy.

DOI PubMed

Epstein-Barr virus (EBV)-encoded small RNA is released from EBV-infected cells and activates signaling from toll-like receptor 3

Iwakiri Dai, Zhou Li, Samanta Mrinal, Matsumoto Misako, Ebihara Takashi, Seya Tsukasa, Imai Shosuke, Fujieda Mikiya, Kawa Keisei, Takada Kenzo

Journal of Experimental Medicine ( Rockefeller University Press )  206 ( 10 ) 2091 - 2099   2009年08月

Epstein-Barr virus-encoded small RNA (EBER) is nonpolyadenylated, noncoding RNA that forms stem-loop structure by intermolecular base-pairing, giving rise to double-stranded RNA (dsRNA)-like molecules, and exists abundantly in EBV-infected cells. Here, we report that EBER induces signaling from the Toll-like receptor 3 (TLR3), which is a sensor of viral double-stranded RNA (dsRNA) and induces type I IFN and proinflammatory cytokines. A substantial amount of EBER, which was sufficient to induce signaling from TLR3, was released from EBV-infected cells, and the majority of the released EBER existed as a complex with a cellular EBER-binding protein La, suggesting that EBER was released from the cells by active secretion of La. Sera from patients with infectious mononucleosis (IM), chronic active EBV infection (CAEBV), and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), whose general symptoms are caused by proinflammatory cytokines contained EBER, and addition of RNA purified from the sera into culture medium induced signaling from TLR3 in EBV-transformed lymphocytes and peripheral mononuclear cells. Furthermore, DCs treated with EBER showed mature phenotype and antigen presentation capacity. These findings suggest that EBER, which is released from EBV-infected cells, is responsible for immune activation by EBV, inducing type I IFN and proinflammatory cytokines. EBER-induced activation of innate immunity would account for immunopathologic diseases caused by active EBV infection.

DOI

樹状細胞TLR3の誘導するNK細胞活性化の分子機構

海老原 敬, 松本 美佐子, 瀬谷 司

補体シンポジウム講演集 ( (一社)日本補体学会 )  46   32 - 33   2009年08月

Functional evolution of the TICAM-1 pathway for extrinsic RNA sensing

Seya, T., Matsumoto, M., Ebihara, T., Oshiumi, H.

Immunological Reviews ( Wiley )  227 ( 1 ) 44 - 53   2009年

DOI

抗腫瘍エフェクター機構とその制御 Spirulina熱水抽出物経口投与による抗腫瘍NK細胞の活性化(Enhancement of antitumor natural killer cell activation by orally administered Spirulina extract in mice)

Akao Yusuke, Ebihara Takashi, Matsumoto Misako, Seya Tsukasa

日本免疫学会総会・学術集会記録 ( (NPO)日本免疫学会 )  38   112 - 112   2008年11月

樹状細胞機能を制御する分子基盤 マウス樹状細胞からのIL-10産生におけるTLR4とTLR2との相乗作用(TLR4 acts in synergy with TLR2 in IL-10 production by murine dendritic cells)

Hirata Noriyuki, Yanagawa Yoshiki, Ebihara Takashi, Seya Tsukasa, Uematsu Satoshi, Akira Shizuo, Hayashi Fumie, Iwabuchi Kazuya, Onoe Kazunori

日本免疫学会総会・学術集会記録 ( (NPO)日本免疫学会 )  38   124 - 124   2008年11月

特殊なリンパ球 NK細胞や他のリンパ球 樹状細胞における新規NK活性化分子の解析(An analysis of new NK-activating molecules on myloid DC)

Ebihara Takashi, Matsumoto Misako, Seya Tsukasa

日本免疫学会総会・学術集会記録 ( (NPO)日本免疫学会 )  38   73 - 73   2008年11月

腫瘍抗原および樹状細胞 樹状細胞におけるTLR3/TICAM-1経路を介したクロスプレゼンテーションの制御(Regulation of dendritic coll cross-presentation induced through the TLR3/TICAM-1 pathway)

Azuma Masahiro, Ebihara Takashi, Kubota Nobuhiko, Akazawa Takashi, Matsumoto Misako, Seya Tsukasa

日本免疫学会総会・学術集会記録 ( (NPO)日本免疫学会 )  38   105 - 105   2008年11月