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Publications (original papers)

New !
Shunsuke Kawamura and Toshiaki Ohteki. Monopoiesis in humans and mice. Int Immunol. 30(11) , 503-509, 2018 Oct 2, doi: 10.1093/intimm/dxy063.

New !
Yusuke Nakanishi, Taku Sato, Kyoko Takahashi and Toshiaki Ohteki. IFN-γ-dependent epigenetic regulation instructs colitogenic monocyte-macrophage lineage defferentiation in vivo. Mucosal Immunol. 11(3), 871-880. 2018 May; doi: 10.1038/mi.2017.104. Epub 2018 Jan 24.

Nobuyuki Onai, Jumpei Asano, Rumiko Kurosaki, Shoko Kuroda, and Toshiaki Ohteki. Flexible fate commitment of E2-2high common DC progenitors implies tuning in tissue microenvironments Int. Immunol. 29, (10), 443-456, (2017) https://doi.org/10.1093/intimm/dxx058

Asano J, Sato T, Ichinose S, Kajita M, Onai, N Shimizu S and Ohteki T. Intrinsic autophage in intestinals stem cells is required for their maintenance and for irradiation-induced intestinal regeneration. Cell Reports 20, (5 ), 1050-1060, (2017) DOI: http://dx.doi.org/10.1016/j.celrep.2017.07.019

Shunsuke Kawamura, Nobuyuki Onai, Fuyuki Miya, Taku Sato, Tatsuhiko Tsunoda, Kazutaka Kurabayashi, Satoshi Yotsumoto, Shoko Kuroda, Katsuto Takenaka, Koichi Akashi and Toshiaki Ohteki. Identification of a human clonogenic progenitor with strict monocyte differentiation potential - a counterpart of mouse cMoPs. Immunity 46 835-848 (2017) doi:10.1016/j. immuni.2017.04.019

Liu J, Guo YM, Onai N, Ohyagi H, Hirokawa M, Takahashi N, Tagawa H, Ubukawa K, Kobayashi I, Tezuka H, Minamiya Y, Ohteki T and Sawada K. Cytosine-phosphorothionate- guanine oligodeoxynucleotides exacerbates hemophagocytosis by inducing tumor necrosis factor-α production in mice after bone marrow transplantation. Biol Blood Marrow Transplant 22, 627-36 (2016) doi: 10.1016/j.bbmt.2015.12.018

Onai N, Ohteki T. Isolation of dendritic cell progenitor and bone marrow progenitor cells from mouse. Methods Mol Biol 1423, 53-9 (2016)doi : 10.1007/978-1-4939-3606-9_4

Yokoi T, Yokoi K, Akiyama K, Higuchi T, Shimada Y, Kobayashi H, Sato T, Ohteki T, Otsu M, Nakauchi H, Ida H and Ohashi T. Non-myeloablative preconditioning with ACK2 (anti-c-Kit antibody) is efficient in bone marrow transplantation for murine models of mucopolysaccharidosis type II. Mol Genet Metab 119, 232-238 (2016) doi:10.1016/J.ymgme.2016.08.003

Kobayashi H, Kobayashi CI, Nakamura-Ishizu A, Karigane D, Haeno H, Yamamoto KN, Sato T, Ohteki T, Hayakawa Y, Barber GN, Kurokawa M, Suda T, and Takubo K.Bacterial c-di-GMP affects hematopoietic stem/progenitors and their niches through STING. Cell Reports 111, 71-84, (2015) doi:10.1016/J.celrep.2015.02.066.

Guilliams M, Ginhoux F, Jakubzick C, Naik S. H, Onai N, Schraml B. U, Segura E, Tussiwand R and Yona S.Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nature Reviews Immunology 14, 571-578(2014) doi:10.1038/nri3712.

Onai N, and Ohteki T. Bipotent or Oligopotent?A macrophage and DC progenitor revisited. Immunity 41, 5-7 (2014) doi: 10.1016/J.immuni.2014.07.004.

Yusuke Nakanishi, Taku Sato, and Toshiaki Ohteki. Commensal Gram-positive bacteria initiates colitis by inducing monocyte/macrophage mobilization. Mucosal Immunol 8, 152-160 (2015) ; doi:10.1038/mi.2014.53.

Aya Yokota-Nakatsuma, Hajime Takeuchi, Yoshiharu Ohoka, Chieko Kato,Si-Young Song, Tomoaki Hoshino, Hideo Yagita, Toshiaki Ohteki, and Makoto Iwata．Retinoic acid prevents mesenteric lymph node dendritic cells from inducing IL-13-producing inflammatory Th2 cells. Mucosal Immunol Jul;7(4):786-801. (2014) doi: 10.1038/mi.2013.96.

Ohyagi H, Onai N, Sato T, Yotsumoto S, Liu J, Akiba H, Yagita H, Atarashi K, Honda K, Roers A, Muller W, Kurabayashi K, Hosoi-Amaike M, Takahashi N, Hirokawa M, Matsushima K, Sawada K, and Ohteki T. Monocyte-derived dendritic cells perform hemophagocytosis to fine-tune excessive immune responses. Immunity 39, 584-598 (2013) doi: 10.1016/J.immuni.2013.06.019.

Sato T, Kitawaki T, Fujita H, Iwata M, Iyoda T, Inaba K, Ohteki T, Hasegawa S, Kawada K, Sakai Y, Ikeuchi H, Nakase H, Niwa A, Takaori-Kondo A, Kadowaki N. Human CD1c+ myeloid dendritic cells acquire a high level of retinoic acid-producing capacity in response to vitamin D3. J Immunol.191, 3152-3160 (2013) doi: 10.4049/jimmunol.1203517.

Hayashi A, Sato T, Kamada N, Mikami Y, Matsuoka K, Hisamatsu T, Hibi T, Roers S, Yagita H, Ohteki T, Oshimura A, Kanai T. A Single train of Clostridium butyricum Induces intestinal IL-10-Producing Macrophages that Suppress Acute Colitis. Cell Host Microbe, 13, 711-722(2013), doi :10.1016/ j.chom. 2013. 05. 013.

Sato T, Ikeda M, Yotsumoto S, Shimada Y, Higuchi T, Kobayashi H, Fukuda T, Ohashi T, Suda T, and Ohteki T. Novel interferon-based pre-transplantation conditioning in the treatment of a congenital metabolic disorder. Blood 121, 3267-3273 (2013), doi: 10.1182/blood-2012-07-443713.

Onai N, Kurabayashi K, Hosoi-Amaike M, Toyama-Sorimachi N, Matsushima K, Inaba, K, and Ohteki T.pA clonogenic progenitor with prominent plasmacytoid dendritic cell developmental potential. Immunity 38, 943-957 (2013) doi: 10.1016/J.immuni.2013.04.006

Ichikawa A, Kuba K, Morita M, Chiba S, Tezuka H, Hara H, Sasaki T, Ohteki T, Ranieri V.M , dos Santos C C, Kawaoka Y, Akira S, Luster A D, Lu B, Penninger J M, Uhlig S , Slutsky A S, and Imai Y. CXCL10-CXCR3 enhances the development of neutrophil-mediated fulminant lung injury of viral and non-viral origin.Am J Respir Crit Care Med 187, 65-77 (2013) doi:10.1164/rccm.201203-0508OC.

Liu J, Guo YM, Hirokawa M, Iwamoto K, Ubukawa K, Michishita Y, Fujishima N, Tagawa H, Takahashi N, Xiao W, Yamashita J, Ohteki T, and Sawada K. A synthetic double-stranded RNA, poly I:C, induces a rapid apoptosis of human CD34+ cells. Exp Hematol 40, 330-341(2012) doi:10.1016/j.exphem.2011.12.002

Mashima H, Sato S, Horie Y, Nakagawa Y, Kojima I,Ohteki T, and Ohnishi H. Interferon regulatory factor-2 regulatesexocytosis mechanisms mediated by SNAREs in pancreatic acinar cells. Gastroenterology 141, 1102-1113 (2011) doi:10.1053/j.gastro.2011.05.051

Tezuka H, Abe Y, Asano J, Sato T, Liu J, Iwata M, and Ohteki T. Qualitative prominence of plasmacytoid dendriticcells in mucosal T cell-independent IgA induction. Immunity 34, 247-257(2011) doi:10.1016/j.immuni.2011.02.002

Asano J, Tada, H, Onai, N, Sato T, Horie Y, Fujimoto Y, Kukase K, Suzuki A, Tak W.M, and Ohteki T. Nucleotide-binding oligomerization domain-like receptor signaling enhances dendritic cell-mediated cross-priming in vivo. J Immunol 184, 736-745 (2010)

Tezuka H, and Ohteki T. Regulation of intestinal homeostasis by dendritic cells.Immunol Rev 234, 247-258 (2010) Review

Sato T, Onai N, Yoshihara H, Arai F, Suda T, and Ohteki T. Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon-dependent exhaustion. Nat Med 15, 696-700 (2009)

Onai N and Manz M.G. The STATs on dendritic cell development. Immunity 28, 490-492 (2008) Review

Onai N, Obata-Onai A, Schmid MA, Ohteki T, Jarrossay D, and Manz MG. Identification of clonogenic common Flt+3M-CSFR+ plasmacytoid and dendritic cell progenitors in mouse bone marrow. Nat Immunol 8, 1207-1216 (2007)

Tezuka H, Abe Y, Iwata M, Takeuchi H, Ishikawa H, Matsushita M, Shiohara T, Akira S, and Ohteki T. Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells. Nature 448, 929-933 (2007)

Ohteki T, Tada H, Ishida K, Sato T, Maki C, Yamada T, Hamuro J, and Koyasu S. Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo. J Exp Med 203, 2329-2338 (2006)

Kuwajima S, Sato T, Ishida K, Tada H, Tezuka H, and Ohteki T. IL-15-dependent cross-talk between cDC and pDC is essential for CpG-induced immune activation. Nat Immunol 7, 740-746 (2006)　

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Toshiaki OHTEKI, Ph.D.
Taku SATO, Ph.D.
Masashi KANAYAMA, Ph.D.
Mihoko KAJITA, Ph.D.
Minako INAZAWA (D4)
Kana MINAMIDE (D4)
Miwako SASE(D4)
Megumi AKIYAMA(D2)
Shun ISHIKAWA(D2)
Yuta IZUMI (D2)
Shota YAMADA(M2)
Tomiki HAYASHI
Kisho SHISEKI
Takaei SHIN
Eriko OHASHI
Mai NAKAGAWA

1. Differentiation and function of dendritic cells
1) Discovery of a novel source of dendritic cells, the control tower of the immune system
Dendritic cells (DCs) maintain immune tolerance under steady-state conditions, and activate immune cells upon infection. We have discovered a novel source of dendritic cells (DCs), considered the “control tower” of the immune system (Immunity 38, 943-57 (2013)). DCs consist of conventional DCs (cDCs) and plasmacytoid DCs (pDCs), both of which play critical regulatory roles in the immune system. In particular, pDCs are characterized by their capacity to produce large amounts of type I interferons (IFNs). This function could be important in medical applications for treating viral infections and autoimmune diseases. In 2007, in collaboration with a research group in Switzerland, we identified progenitor cells committed to the DC lineage for the first time. However, these progenitors gave rise to many more cDCs than pDCs, implying that there must be another unidentified type of DC progenitor that serves as a major source of pDCs. This time, we successfully identified a DC progenitor with prominent pDC differentiation potential. The number of pDCs generated from the new DC progenitor cells is several times higher than that from the previously reported DC progenitor. Importantly, the new DC progenitor highly expresses E2-2, an essential transcription factor for pDC development. In addition, this progenitor never gives rise to cells outside the DC lineage. Based on our findings, we designate them together by the term, common DC progenitors (CDPs) (Fig. 1). The identification of DC progenitors that produce 500-1,000 DCs and no other hematopoietic cells may be valuable in the development of therapeutic applications for infectious diseases, cancers, and autoimmune diseases.

2) Discovery of a novel function of dendritic cells to fine-tune excessive immune responses
An immune response is a double-edged sword that simultaneously defends and injures the host; the more severe the infection, the greater the regulatory control must be. We have discovered a novel function of dendritic cells (DCs) for fine-tuning excessive immune responses in vivo. In addition to cDCs and pDCs, DCs may be derived from inflammatory monocytes (monocyte-derived DCs, Mo-DCs), especially under inflammatory conditions. The present study demonstrated that, during severe viral infections, Mo-DCs engulfed apoptotic erythroid cells in a process called hemophagocytosis, which is a characteristic of hemophagocytic syndrome (HPS). Importantly, hemophagocytosis was required for Mo-DCs to produce interleukin-10 (IL-10), an important immunoregulatory cytokine, thereby fine-tuning the immune responses to limit self-damage and ensure the host’s survival (Immunity 39, 584-98 (2013)). These results point to hemophagocytosis as a mechamism that ensures the host’s survival by preventing excessive immune response-mediated damage, instead allowing the virus to persist in the host under conditions of severe viral infection. In summary, our findings indicate that hemophagocytosis is induced by TLR ligands or viruses in sequential steps (Fig. 2) to suppress potentially damaging immune responses.

2. Understanding of tissue homeostasis on the basis of immune cell-tissue stem cell interplay
We recently found that type I IFNs induce proliferation and exhaustion in hematopoietic stem cells (HSCs), and that interferon regulatory factor-2 (IRF2), a transcriptional suppressor of type I IFN signaling, preserves the self-renewal and multi-lineage differentiation capacity of HSCs (Nat Med 15, 696-700 (2009)). Based on this finding, we show that type I IFN preconditioning, without irradiation or DNA alkylating agents, significantly enhanced the HSC engraftment efficiency in wild type (WT) recipient mice, which was applicable to the treatmen-glucuronidase deficiency, in which it restored enzyme expression at the HSC level. Our findings suggest type I IFN-based preconditioning, combined with HSC transplantation, as a novel non-genotoxic treatment for some congenital diseases (Blood 121, 3263-73 (2013)).

Our research projects focus on understanding the dynamic maintenance and transfiguration of homeostasis in the living body. Our goal is to define the homeostasis mechanism under conditions of health and disease. To accomplish this goal, we are trying to clarify the molecular basis of induction and failure of homeostasis by focusing on immune cells in particular mononuclear phagocytes (dendritic cells and macrophages), tissue stem cells, and their functional interplay in the immunological and non-immunological organs, such as skin and intestine. On the basis of our findings, we will further pursue our research in the hope of developing new rational therapies for prevention and treatment of disease.

Main Projects
1. Progenitors of mononuclear phagocytes (dendritic cells & macrophages) and its application to disease treatment
2. Elucidation of mononuclear phagocyte functions in inflammatory bowel diseases
3. Regulatory mechanisms of tissue homeostasis by tissue stem cells in the blood, intestine, and skin
4. Understanding of tissue homeostasis on the basis of stem cell-immune cell interplay

 

Department of Biodefense Research Medical Research Institute, Tokyo Medical and Dental University

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M&D Tower 19F, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan

ohteki.bre"a"mri.tmd.ac.jp

Professor

Toshiaki OHTEKI, Ph D.

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LAST UPDATE 2020.04.01