研究等業績 - 原著論文 - 海老原 敬
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TIGIT mediates activation-induced cell death of ILC2s during chronic airway allergy.
Toshiki Yamada, Megumi Tatematsu, Shunsuke Takasuga, Akane Fuchimukai, Kenki Yamagata, Shinsuke Seki, Keiji Kuba, Hideyuki Yoshida, Ichiro Taniuchi, Günter Bernhardt, Kazuko Shibuya, Akira Shibuya, Takechiyo Yamada, Takashi Ebihara
The Journal of experimental medicine ( The Journal of experimental medicine ) 220 ( 7 ) 2023年07月 [査読有り]
研究論文（学術雑誌） 国際共著
While group-2 innate lymphoid cells (ILC2s) are highly proliferative in allergic inflammation, the removal of overactivated ILC2s in allergic diseases has not been investigated. We previously showed that chronic airway allergy induces "exhausted-like" dysfunctional ILC2s expressing T cell immunoreceptor with Ig and ITIM domains (TIGIT). However, the physiological relevance of these cells in chronic allergy remains elusive. To precisely identify and monitor TIGIT+ ILC2s, we generated TIGIT lineage tracer mice. Chronic allergy stably induced TIGIT+ ILC2s, which were highly activated, apoptotic, and were quickly removed from sites of chronic allergy. Transcripts from coding genes were globally suppressed in the cells, possibly due to reduced chromatin accessibility. Cell death in TIGIT+ ILC2s was enhanced by interactions with CD155 expressed on macrophages, whereas genetic ablation of Tigit or blockade by anti-TIGIT antagonistic antibodies promoted ILC2 survival, thereby deteriorating chronic allergic inflammation. Our work demonstrates that TIGIT shifts the fate of ILC2s toward activation-induced cell death, which could present a new therapeutic target for chronic allergies.
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A mutant BCL11B-N440K protein interferes with BCL11A function during T lymphocyte and neuronal development
Kazuki Okuyama, Motoi Yamashita, Artemis Koumoundourou, Christoph Wiegreffe, Michiko Ohno-Oishi, Samuel J. H. Murphy, Xin Zhao, Hideyuki Yoshida, Takashi Ebihara, Naoko Satoh-Takayama, Satoshi Kojo, Hiroshi Ohno, Tomohiro Morio, Yibo Wu, Jennifer Puck, Hai-Hui Xue, Stefan Britsch, Ichiro Taniuchi
Nature Immunology 2024年11月
研究論文（学術雑誌）
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FoxD1 expression identifies a distinct subset of hepatic stellate cells involved in liver fibrosis
Kenki Yamagata, Shunsuke Takasuga, Megumi Tatematsu, Akane Fuchimukai, Toshiki Yamada, Masaru Mizuno, Mayako Morii, Takashi Ebihara
Biochemical and Biophysical Research Communications ( Biochemical and Biophysical Research Communications ) 734 2024年11月
研究論文（学術雑誌）
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Dysfunction of type 1 and type 2 immune cells: a lesson from exhausted-like ILC2s and their activation-induced cell death.
Ebihara T, Yamada T, Fuchimukai A, Takasuga S, Endo T, Yamada T, Tatematsu M
International immunology 2024年05月
研究論文（学術雑誌）
The concept of immune cell exhaustion/dysfunction has developed mainly to understand impaired type 1 immune responses especially by CD8 T cells against tumors or virus-infected cells and has been applied to other lymphocytes. Natural killer (NK) cells and CD4 T cells support the efficient activation of CD8 T cells but exhibit a dysfunctional phenotype in tumor microenvironments and in chronic virus infections. In contrast, the concept of type 2 immune cell exhaustion/dysfunction is poorly established. Group 2 innate lymphoid cells (ILC2s) and T-helper 2 (Th2) cells are the major lymphocyte subsets that initiate and expand type 2 immune responses for antiparasitic immunity or allergy. In mouse models of chronic parasitic worm infections, Th2 cells display impaired type 2 immune responses. Chronic airway allergy induces exhausted-like ILC2s that quickly fall into activation-induced cell death to suppress exaggerated inflammation. Thus, the modes of exhaustion/dysfunction are quite diverse and rely on the types of inflammation and the cells. In this review, we summarize current knowledge of lymphocyte exhaustion/dysfunction in the context of type 1 and type 2 immune responses and discuss ILC2-specific regulatory mechanisms during chronic allergy.
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CD45 alleviates airway inflammation and lung fibrosis by limiting expansion and activation of ILC2s.
Guangwei Cui, Akihiro Shimba, Jianshi Jin, Nozomi Hojo, Takuma Asahi, Shinya Abe, Aki Ejima, Shinri Okada, Keizo Ohira, Ryoma Kato, Shizue Tani-Ichi, Ryo Yamada, Takashi Ebihara, Katsuyuki Shiroguchi, Koichi Ikuta
Proceedings of the National Academy of Sciences of the United States of America 120 ( 36 ) e2215941120 2023年09月 [査読有り]
研究論文（学術雑誌） 国際共著
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Yui Miyabe, Hiroki Tomizawa, Hidekazu Saito, Toshiki Yamada, Kazuhiro Shiina, Koh Koizumi, Yohei Kawasaki, Shinsuke Suzuki, Mineyo Fukuchi, Shigeharu Ueki, Takashi Ebihara, Takechiyo Yamada
Allergy ( Wiley ) 77 ( 10 ) 3154 - 3156 2022年10月 [査読有り]
研究論文（学術雑誌）
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今月の特集1 自然免疫を担うリンパ球たち 抗原受容体をもたないリンパ球 NK細胞
海老原 敬
臨床検査 ( 株式会社医学書院 ) 66 ( 5 ) 582 - 587 2022年05月 [招待有り]
研究論文（学術雑誌）
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An J.
Oncogene ( Oncogene ) 2022年 [査読有り]
研究論文（学術雑誌）
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Trained innate lymphoid cells in allergic diseases
Ebihara Takashi, Tatematsu Megumi, Fuchimukai Akane, Yamada Toshiki, Yamagata Kenki, Takasuga Shunsuke, Yamada Takechiyo
Allergology International ( 一般社団法人日本アレルギー学会 ) 70 ( 2 ) 174 - 180 2021年 [査読有り] [招待有り]
研究論文（学術雑誌）
<p>Group 2 innate lymphoid cells (ILC2s) reside in peripheral tissues such as the lungs, skin, nasal cavity, and gut and provoke innate type 2 immunity against allergen exposure, parasitic worm infection, and respiratory virus infection by producing T<sub>H</sub>2 cytokines. Recent advances in understanding ILC2 biology revealed that ILC2s can be trained by IL-33 or allergic inflammation, are long-lived, and mount memory-like type 2 immune responses to any other allergens afterwards. In contrast, IL-33, together with retinoic acid, induces IL-10-producing immunosuppressive ILC2s. In this review, we discuss how the allergic cytokine milieu and other immune cells direct the generation of trained ILC2s with immunostimulatory or immunosuppressive recall capability in allergic diseases and infections associated with type 2 immunity. The molecular mechanisms of trained immunity by ILCs and the physiological relevance of trained ILC2s are also discussed.</p>
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Dichotomous Regulation of Acquired Immunity by Innate Lymphoid Cells
Ebihara T.
Cells ( Cells ) 9 ( 5 ) 2020年05月 [査読有り] [招待有り]
研究論文（学術雑誌） 単著
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Exhausted-like Group 2 Innate Lymphoid Cells in Chronic Allergic Inflammation
Ebihara T, Taniuchi I
Trends in Immunology ( Trends in Immunology ) 40 ( 12 ) 1095 - 1104 2019年12月 [査読有り] [招待有り]
研究論文（学術雑誌） 国内共著
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Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis.
Amanda Ardain, Racquel Domingo-Gonzalez, Shibali Das, Samuel W. Kazer, Nicole C. Howard, Alveera Singh, Mushtaq Ahmed, Shepherd Nhamoyebonde, Javier Rangel-Moreno, Paul Ogongo, Lan Lu, Duran Ramsuran, Maria de la Luz GarciaHernandez, Tyler Ulland, Matthew Darby, Eugene Park, Farina Karim, Laura Melocchi, Rajhmun Madansein, Kaylesh Jay Dullabh, Micah Dunlap, Nancy MarinAgudelo, Takashi Ebihara, Thumbi Ndung’u, Deepak Kaushal, Alexander S. Pym, Jay K. Kolls, Adrie Steyn, Joaquín Zúñiga, William Horsnel, Wayne Yokoyama, Alex K. Shalek, Henrik N. Kløverpris, Marco Colonna, Alasdair Leslie, Shabaana A. Khader
Nature 2019年06月 [査読有り]
研究論文（学術雑誌） 国際共著
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Transcription factors in the development and function of group 2 innate lymphoid cells
Ebihara T, Taniuchi I
International Journal of Molecular Sciences ( International Journal of Molecular Sciences ) 20 ( 6 ) 2019年03月 [査読有り] [招待有り]
研究論文（学術雑誌） 国内共著
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Runx/Cbfb complexes protect group 2 innate lymphoid cells from exhausted-like hyporesponsiveness during allergic airway inflammation.
Chizuko Miyamoto, Satoshi Kojo, Motoi Yamashita, Kazuyo Moro, Georges Lacaud, Katsuyuki Shiroguchi, Ichiro Taniuchi, Takashi Ebihara*
Nature Communications 2019年01月 [査読有り]
研究論文（学術雑誌） 国際共著
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Ardain, A., Domingo-Gonzalez, R., Das, S., Kazer, S.W., Howard, N.C., Singh, A., Ahmed, M., Nhamoyebonde, S., Rangel-Moreno, J., Ogongo, P., Lu, L., Ramsuran, D., de la Luz Garcia-Hern, ez, M., Ull, , T.K., Darby, M., Park, E., Karim, F., Melocchi, L., Madansein, R., Dullabh, K.J., Dunlap, M., Marin-Agudelo, N., Ebihara, T., Ndung?u, T., Kaushal, D., Pym, A.S., Kolls, J.K., Steyn, A., Z{\'u}{\~n}iga, J., Horsnell, W., Yokoyama, W.M., Shalek, A.K., Kl?verpris, H.N., Colonna, M., Leslie, A., Khader, S.A.
Nature ( Nature ) 572 ( 7768 ) 2019年
研究論文（学術雑誌）
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Cbfβ2 controls differentiation of and confers homing capacity to prethymic progenitors.
Mari Tenno, Satoshi Kojo, Divine-Fondzenyuy Lawir, Isabell Hess, Katsuyuki Shiroguchi, Takashi Ebihara, Takaho A Endo, Sawako Muroi, Rumi Satoh, Hiroshi Kawamoto, Thomas Boehm, Ichiro Taniuchi
Journal of Experimental Medicine 2018年02月 [査読有り]
研究論文（学術雑誌） 国際共著
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Immunoreceptor tyrosine-based inhibitory motif-dependent functions of an MHC class I-specific NK cell receptor.
Michael D Bern, Diana L Beckman, Takashi Ebihara, Samantha M Taffner, Jennifer Poursine-Laurent, J Michael White, Wayne M Yokoyama
Proc Natl Acad Sci U S A 2017年10月 [査読有り]
研究論文（学術雑誌） 国内共著
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Runx3 specifies lineage commitment of innate lymphoid cells
Takashi Ebihara, Christina Song, Stacy H Ryu, Beatrice Plougastel-Douglas, Liping Yang, Ditsa Levanon, Yoram Groner, Michael D Bern, Thaddeus S Stappenbeck, Marco Colonna, Takeshi Egawa, Wayne M Yokoyama
Nature Immunology 2015年11月 [査読有り]
研究論文（学術雑誌） 国際共著
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Runx3 specifies lineage commitment of innate lymphoid cells
Takashi Ebihara, Christina Song, Stacy H Ryu, Beatrice Plougastel-Douglas, Liping Yang, Ditsa Levanon, Yoram Groner, Michael D Bern, Thaddeus S Stappenbeck, Marco Colonna, Takeshi Egawa, Wayne M Yokoyama
Nature Immunology ( Springer Nature ) 16 ( 11 ) 1124 - 1133 2015年09月 [査読有り]
研究論文（学術雑誌）
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Natural killer cell licensing in mice with inducible expression of MHC class I
Ebihara, T., Jonsson, A.H., Yokoyama, W.M.
Proceedings of the National Academy of Sciences of the United States of America 110 ( 45 ) 2013年 [査読有り]
研究論文（学術雑誌）
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Ebihara Takashi, Azuma Masahiro, Oshiumi Hiroyuki, Kasamatsu Jun, Iwabuchi Kazuya, Matsumoto Kenji, Saito Hirohisa, Taniguchi Tadatsugu, Matsumoto Misako, Seya Tsukasa
Journal of Experimental Medicine ( Rockefeller University Press ) 207 ( 12 ) 2675 - 2687 2010年 [査読有り]
研究論文（学術雑誌）
In myeloid dendritic cells (mDCs), TLR3 is expressed in the endosomal membrane and interacts with the adaptor toll/interleukin 1 receptor homology domain-containing adaptor molecule 1 (TICAM-1; TRIF). TICAM-1 signals culminate in interferon (IFN) regulatory factor (IRF) 3 activation. Co-culture of mDC pretreated with the TLR3 ligand polyI:C and natural killer (NK) cells resulted in NK cell activation. This activation was triggered by cell-to-cell contact but not cytokines. Using expression profiling and gain/loss-of-function analyses of mDC genes, we tried to identify a TICAM-1-inducing membrane protein that participates in mDC-mediated NK activation. Of the nine candidates screened, one contained a tetraspanin-like sequence and satisfied the screening criteria. The protein, referred to as IRF-3-dependent NK-activating molecule (INAM), functioned in both the mDC and NK cell to facilitate NK activation. In the mDC, TICAM-1, IFN promoter stimulator 1, and IRF-3, but not IRF-7, were required for mDC-mediated NK activation. INAM was minimally expressed on NK cells, was up-regulated in response to polyI:C, and contributed to mDC-NK reciprocal activation via its cytoplasmic tail, which was crucial for the activation signal in NK cells. Adoptive transfer of INAM-expressing mDCs into mice implanted with NK-sensitive tumors caused NK-mediated tumor regression. We identify a new pathway for mDC-NK contact-mediated NK activation that is governed by a TLR signal-derived membrane molecule.
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Hepatitis C virus–infected hepatocytes extrinsically modulate dendritic cell maturation to activate T cells and natural killer cells
Takashi Ebihara, Masashi Shingai, Misako Matsumoto, Takaji Wakita, Tsukasa Seya
Hepatology ( Wiley ) 48 ( 1 ) 48 - 58 2008年07月 [査読有り]
研究論文（学術雑誌）
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Ebihara, T., Masuda, H., Akazawa, T., Shingai, M., Kikuta, H., Ariga, T., Matsumoto, M., Seya, T.
International Immunology 19 ( 10 ) 1145 - 55 2007年 [査読有り]
研究論文（学術雑誌）
Monocyte-derived dendritic cells (mDCs) and NK cells are reciprocally activate via cytokines and cell-cell contact. Although seven human NKG2D ligands (NKG2DLs), UL16-binding proteins (ULBP) 1, 2, 3 and 4, retinoic acid early transcript 1G (RAET1G) and MHC class I-related chains A and B, have been reported, the differential distribution and roles of these ligands in the maturation of human mDCs have not been elucidated. In the present study, we produced polyclonal antibodies (pAbs) directed against human ULBP1, 2 and 3. All these ULBPs were detected on human mDCs when probed by the pAbs, although their expression profiles were different. We next investigated what kinds of Toll-like receptor agonists and RNA viruses [influenza virus, human respiratory syncytial virus (RSV), measles virus and hepatitis C virus (HCV)] induced the expression of NKG2DLs on mDCs. ULBP1 was up-regulated on mDCs in response to LPS or infection with RSV. The expression of ULBP2 was induced by LPS and poly I:C, indicating that the TIR-containing adapter molecule-1 (TIR domain-containing adaptor-inducing IFN) pathway is associated with ULBP2 induction. Although infection with HCV did not cause up-regulation of NKG2DLs, other RNA virus infections and poly I:C promoted expression of ULBP2 and RAET1G in an IFN-alpha/beta-independent manner. Finally, the over-expression of ULBP1 and 2 on mDCs facilitated NK cell proliferation and IFN-gamma production through a mDC-NK cell interaction in the presence of IL-2. Hence, the results reflect the important role of NKG2DLs on human mDCs in mDC-mediated NK cell activation.
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Human Metapneumovirus Infection in Japanese Children
Ebihara, T., Endo, R., Kikuta, H., Ishiguro, N., Ishiko, H., Hara, M., Takahashi, Y., Kobayashi, K.
Journal of Clinical Microbiology ( American Society for Microbiology ) 42 ( 1 ) 126 - 132 2004年 [査読有り]
研究論文（学術雑誌）
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Seroprevalence of human metapneumovirus in Japan
Takashi Ebihara, Rika Endo, Hideaki Kikuta, Nobuhisa Ishiguro, Mikio Yoshioka, Xiaoming Ma, Kunihiko Kobayashi
Journal of Medical Virology ( Wiley ) 70 ( 2 ) 281 - 283 2003年06月 [査読有り]
研究論文（学術雑誌）