内因性リガンドに対する樹状細胞応答機構の解明

2013 Fiscal Year Annual Research Report

• Project Area: Homeostatic inflammation: Molecular basis and dysregulation
• Project/Area Number: 21117003
• Research Institution: Osaka University
• Principal Investigator: 改正 恒康 大阪大学, 免疫学フロンティア研究センター, 招へい教授 (60224325)
• Project Period (FY): 2009-04-01 – 2015-03-31
• Keywords: 樹状細胞 / 自然免疫 / 病原体センサー / 炎症

Outline of Annual Research Achievements

非感染性慢性炎症を制御する機構の解明を、分子レベル、細胞レベル、個体レベルで進めている。分子レベルでは、炎症に関与する転写因子NF-κBを制御する分子機構の解析を行った。これまでにユビキチンリガーゼPDLIM2が核内でNF-κBのp65サブユニットをユビキチン化して分解すること、すなわちPDLIM2による炎症制御機構を見出していたが、さらに、その作用にシャペロンタンパクHSP70が関与することを明らかにした。HSP70は、転写因子NF-κB の活性化後に発現が増強し、核内へ移行した。そして、PDLIM2とプロテアーゼ関連分子BAG1に結合することにより、NF-κBのp65サブユニットの分解を促進した。また、HSP70あるいはBAG1の欠損マウス由来の樹状細胞において、PDLIM2欠損マウス由来の樹状細胞と同様に、炎症性サイトカインの産生亢進が認められた。これらの結果から、HSP70による転写因子分解を介した炎症制御という新規の分子機構が明らかになった。また、細胞レベルでは、死細胞を取り込む活性、および細胞傷害性T細胞分化誘導活性の強い樹状細胞サブセット、CD8α陽性樹状細胞（CD8α＋DC)に着目した。これまでに、CD8α＋DCを一時的に欠失させることのできるマウス（XCR1-DTRvenusマウス）を作成していたが、さらにCD8α＋DCを恒常的に欠失させるマウス（XCR1-DTAマウス）を作成し、その樹状細胞サブセットの個体レベルでの機能的意義の解明を試みた。そして、このマウスにおいて、腸管のT細胞が著明に減少し、化学物質誘導型の腸炎症状が増悪していることを見出した。この結果から、免疫恒常性を制御する、CD8α＋DCの新規の機能的意義が示唆された。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Transcription factor IRF8 plays a critical role in the development of murine basophils and mast cells. (2015)
  • Author(s): H. Sasaki, D. Kurotaki, N. Osato, H. Sato, I. Sasaki, S. Koizumi, H. Wang, C. Kaneda, A. Nishiyama, T. Kaisho, H. Aburatani, H. C. Morse III, K. Ozato, T. Tamura.
  • Journal Title: Blood Volume: 125(2) Pages: 358-369
  • DOI: http://dx.doi.org/10.1182/blood-2014-02-557983
  • Peer Reviewed
• [Journal Article] Transcriptional Control of dendritic cell differentiation. (2014)
  • Author(s): I. Sasaki, T. Kaisho
  • Journal Title: Curr. Top. Microbiol. Immunol. Volume: 381 Pages: 257-278
  • DOI: 10.1007/82_2014_378
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Homeostatic inflammation in innate immunity. (2014)
  • Author(s): K. Miyake, T. Kaisho
  • Journal Title: Curr.Opin. Immunol. Volume: 30 Pages: 85-90
  • DOI: 10.1016/j.coi.2014.08.003
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Olfactory plays a key role in spatiotemporal pathogenesis of cerebral malaria. (2014)
  • Author(s): H. Zhao, T. Aoshi, S. Kawai, Y. Mori, A. Konishi, M. Ozkan, Y. Fujita, Y. Haseda, M. Shimizu, M. Kohyama, K. Kobiyama, K. Eto, J. Nabekura, T. Horii, T. Ishino, M. Yuda, H. Hemmi, T. Kaisho, S. Akira, M. Kinoshita, K. Tohyama, Y. Yoshioka, K. J. Ishii, C. Coban
  • Journal Title: Cell Host Microbe Volume: 15 Pages: 551-563
  • DOI: http://dx.doi.org/10.1016/j.chom.2014.04.008
  • Peer Reviewed
• [Journal Article] Single-cell imaging of caspase-1 dynamics reveals an all-or-none inflammasome signaling response. (2014)
  • Author(s): T. Liu, Y. Yamaguchi, Y. Shirasaki, K. Shikada, M. Yamagishi, K. Hoshino, T. Kaisho, K. Takemoto, T. Suzuki, E. Kuranaga, O. Ohara, M. Miura.
  • Journal Title: Cell Reports Volume: 8 Pages: 974-982
  • DOI: http://dx.doi.org/10.1016/j.celrep.2014.07.012
  • Peer Reviewed
• [Journal Article] IL-27 affects helper T cell responses via regulation of PGE2 production by macrophages. (2014)
  • Author(s): Y. Sato, H. Hara, T. Okuno, N. Ozaki, S. Suzuki, T. Yokomizo, T. Kaisho, H. Yoshida.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 451 Pages: 215-221
  • DOI: 10.1016/j.bbrc.2014.07.096
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Homeostasis of thymus-derived Foxp3+ regulatory T cells is controlled by ultraviolet B exposure in the skin. (2014)
  • Author(s): S. Yamazaki, A. Nishioka, S. Kasuya, N. Ohkura, H. Hemmi, T. Kaisho, O. Taguchi, S. Sakaguchi, A. Morita
  • Journal Title: J Immunol Volume: 193(11) Pages: 5488-97
  • DOI: 10.4049/jimmunol.1400985
  • Peer Reviewed
• [Journal Article] Limitation of immune tolerance-inducing thymic epithelial cell development by Spi-B-mediated negative feedback regulation. (2014)
  • Author(s): N. Akiyama, M. Shinzawa, M. Miyauchi, H. Yanai, R. Tateishi, Y. Shimo, D. Ohshima, K. Matsuo, I. Sasaki, K.Hoshino, G. Wu, S. Yagi, J. Inoue, T. Kaisho, T. Akiyama
  • Journal Title: J. Exp. Med Volume: 211 Pages: 2425-2438
  • DOI: 10.1084/jem.20140825
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] HSP70 mediates degradation of the p65 subunit of nuclear factor κB to inhibit inflammatory signaling (2014)
  • Author(s): T. Tanaka, A. Shibazaki, R. Ono, T. Kaisho
  • Journal Title: Sci. Signal Volume: 7(356) Pages: ra119
  • DOI: 10.1126/scisignal.2005533
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Innate immunity and allergy. (2013)
  • Author(s): T. Kaisho
  • Journal Title: Allergy Volume: 62(7) Pages: 789-796
• [Presentation] Intestinal Immune Homeostasis Regulated by Dendritic Cells. (2015)
  • Author(s): 改正恒康
  • Organizer: The 3rd Homeostatic Inflammation International Symposium
  • Place of Presentation: 東京大学医科学研究所（東京都、港区）
  • Year and Date: 2015-01-31 – 2015-01-31
  • Invited
• [Presentation] Roles of ArginaseⅠ in Cholera toxin-induced production of proinflammatory cytokines. (2014)
  • Author(s): I. Sasaki, S. Fukuda, T. Orimo, H. Hemmi, T. Kaisho.
  • Organizer: 第43回日本免疫学会総会;学術集会記録43:99, 2014
  • Place of Presentation: 京都国際会館（京都府、京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Homeostasis of thymus-derived Foxp3+ regulatory T cells is controlled by ultraviolet B exposure in the skin. (2014)
  • Author(s): S. Yamazaki, A. Nishioka, T. Kaisho, O. Taguchi, S. Sakaguchi, A.Morita.
  • Organizer: 第43回日本免疫学会総会;学術集会記録43:176, 2014
  • Place of Presentation: 京都国際会館（京都府、京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] XCL1 and XCR1 are involved in intestinal immne homeostasis by dendritic cells. (2014)
  • Author(s): 1T. Ohta, S. Okura, H. Hemmi, M. Sugiyama, I. Sasaki, C. Yamazaki, K. Hoshino, T. Kaisho.
  • Organizer: 第43回日本免疫学会総会;学術集会記録43:203, 2014
  • Place of Presentation: 京都国際会館（京都府、京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Resistance to a helminthic infection is dependent on mast cell activation mediated by ATP in Spi-B-deficient mice. (2014)
  • Author(s): C. Shimokawa, T. Kanaya, K. Ishiwata, Y. Kurashima, H. Kiyono, T. Kaisho, H. Ohno.
  • Organizer: 第43回日本免疫学会総会;学術集会記録43:213, 2014
  • Place of Presentation: 京都国際会館（京都府、京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] 樹状細胞を介した新規の生体恒常性維持機構 (2014)
  • Author(s): 改正恒康
  • Organizer: 第50回高血圧関連疾患モデル学会学術総会
  • Place of Presentation: 和歌山県立医科大学（和歌山県、和歌山市）
  • Year and Date: 2014-12-05 – 2014-12-05
  • Invited
• [Presentation] Regulatory mechanisms for inflammatory cytokine production by metabolic pathways. (2014)
  • Author(s): 改正恒康
  • Organizer: 第87回日本生化学会大会 The 87th Annual Meeting of the Japanese Biochemical Society
  • Place of Presentation: 京都国際会館（京都府、京都市）
  • Year and Date: 2014-10-16 – 2014-10-16
  • Invited
• [Presentation] In vivo roles of XCR1-expressing dendritic cells. (2013)
  • Author(s): T.Kaisho
  • Organizer: The 42th Annual Meeting of The Japanese Society for Immunology
  • Place of Presentation: 幕張メッセ（千葉県、千葉市）
  • Year and Date: 2013-12-11 – 2013-12-13
  • Invited
• [Presentation] The transcription factor IRF8 is required for basophil development. (2013)
  • Author(s): H. Sasaki, D. Kurotaki, N. Osato, I. Sasaki, C. Kaneda, A. Nishiyama, T.Kaisho, H. C. III. Morse, K. Ozato, T. Tamura.
  • Organizer: 第42回日本免疫学会総会;学術集会記録42:80, 2013
  • Place of Presentation: 幕張メッセ（千葉県、千葉市）
  • Year and Date: 2013-12-11 – 2013-12-13
• [Presentation] Double-stranded RNA of intestinal commensal but not pathogenic bacteria triggers production of protective IFN-β. (2013)
  • Author(s): T. Kawashima, H Yan, Z. Guo, J. Carreras, R. Uchiyama, R. Fukui, T. Kaisho, S. Akira, K. Miyake, H. Tsutsui, T. Saito, N.M.Tsuji.
  • Organizer: 第42回日本免疫学会総会;学術集会記録42:123, 2013
  • Place of Presentation: 幕張メッセ（千葉県、千葉市）
  • Year and Date: 2013-12-11 – 2013-12-13
• [Presentation] A novel mechanism to generate the intestinal intraepithelial T lymphocytes by XCR-expressing dendric cells. (2013)
  • Author(s): T. Ohta, H. Hemmi, C. Yamazaki, M. Sugiyama, I. Sasaki, K. Hoshino, T. Kaisho.
  • Organizer: 第42回日本免疫学会総会;学術集会記録42:124, 2013
  • Place of Presentation: 幕張メッセ（千葉県、千葉市）
  • Year and Date: 2013-12-11 – 2013-12-13
• [Presentation] Function of XCR1-expressing dendric cells in oral tolerance. (2013)
  • Author(s): H. Hemmi, M. Sugiyama, T. Ohta, I. Sasaki, C. Yamazaki, T. Tanaka, K. Hoshino, T. Kaisho.
  • Organizer: 第42回日本免疫学会総会;学術集会記録42:163, 2013
  • Place of Presentation: 幕張メッセ（千葉県、千葉市）
  • Year and Date: 2013-12-11 – 2013-12-13
• [Presentation] Long-term memory T cell response induced by adjuvant role of iNKT cells. (2013)
  • Author(s): K. Shimizu, Y. Sato, J. Shinga, M. Asakura, T. Kaisho.
  • Organizer: 第42回日本免疫学会総会;学術集会記録42:163, 2013
  • Place of Presentation: 幕張メッセ（千葉県、千葉市）
  • Year and Date: 2013-12-11 – 2013-12-13
• [Presentation] Lactococcus lactis subsp. cremoris FC triggers IFN -γ production from NK and T cells via IL-12 and IL-18. (2013)
  • Author(s): Kosaka, H. Yan, H. Tsutsui, T. Kaisho, N. Tsuji.
  • Organizer: 第42回日本免疫学会総会;学術集会記録42:165, 2013
  • Place of Presentation: 幕張メッセ（千葉県、千葉市）
  • Year and Date: 2013-12-11 – 2013-12-13
• [Presentation] The role of M cells in intestinal helminthic infection. (2013)
  • Author(s): C. Shimokawa, T. Kanaya, T. Kaisho.
  • Organizer: 第42回日本免疫学会総会;学術集会記録42:211, 2013
  • Place of Presentation: 幕張メッセ（千葉県、千葉市）
  • Year and Date: 2013-12-11 – 2013-12-13
• [Presentation] Critical in vivo roles of dendritic cells expressing a chemokine receptor, XCR1. (2013)
  • Author(s): T.Kaisho
  • Organizer: The 2013 Fall Conference of the Korean Association of Immunologists
  • Place of Presentation: Seoul（Korea）
  • Year and Date: 2013-11-07 – 2013-11-08
  • Invited
• [Presentation] Molecular mechanisms for dendritic cell subset functions. (2013)
  • Author(s): T. Kaisho.
  • Organizer: Agricultural Biotechnology Symposium ‘Immune Modulation and Bioconvergence
  • Place of Presentation: Seoul（Korea）
  • Year and Date: 2013-11-06 – 2013-11-06
• [Presentation] Enhanced apoptosis by disruption of the STAT3-IκBζ signaling pathway in epithelial cells induces Sjoegren”s syndrome-like autoimmune diseases. (2013)
  • Author(s): A. Okuma, K. Hoshino, T. Kaisho, T. Muta.
  • Organizer: The 15th International Congress of Immunology
  • Place of Presentation: Milan（Italy）
  • Year and Date: 2013-08-22 – 2013-08-27
• [Presentation] In vivo roles of XC chemokine receptor 1-expressing dendritic cells. (2013)
  • Author(s): T. Ohta, H. Hemmi, C. Yamazaki, M. Sugiyama, I. Sasaki, K. Hoshino, T. Kaisho.
  • Organizer: The 15th International Congress of Immunology
  • Place of Presentation: Milan（Italy）
  • Year and Date: 2013-08-22 – 2013-08-27
• [Presentation] In vivo roles of dendritic cells expressing a chemokine receptor, XCR1. (2013)
  • Author(s): T. Kaisho.
  • Organizer: France-Japan Joint Forum “Frontiers in Innate Immunity''
  • Place of Presentation: Strasbourg（France）
  • Year and Date: 2013-06-05 – 2013-06-08
  • Invited
• [Presentation] IL-27 affects helper T cell response via regulation of PGE2 production by macrophages. (2013)
  • Author(s): Y. Sato, H. Hara, S. Suzuki, T. Kaisho and H. Yoshida.
  • Organizer: The Joint international Meeting of The 78th Meeting of the Japanese Society of Interferon and Cytokine Research and The 21st International Symposium on Molecular Cell Biology of Macrophage
  • Place of Presentation: 都市センターホテル（東京都、千代田区）
  • Year and Date: 2013-05-20 – 2013-05-21
• [Presentation] Critical roles of dendritic cells expressing a chemokine receptor XCR1. (2013)
  • Author(s): T. Kaisho, H. Hemmi, M. Sugiyama, T. Ohta.
  • Organizer: The Joint international Meeting of The 78th Meeting of the Japanese Society of Interferon and Cytokine Research and The 21st International Symposium on Molecular Cell Biology of Macrophage
  • Place of Presentation: 都市センターホテル（東京都、千代田区）
  • Year and Date: 2013-05-20 – 2013-05-21
  • Invited
• [Book] Principles of innate immunity, in Sixth Edition Rheumatology vol.1 (2013)
  • Author(s): T. Kaisho, S. Akira.
  • Total Pages: 127-133
  • Publisher: MOSBY, ELSEVIER
• [Remarks] 改正研究室 研究業績2013年
  • URL: http://immreg.ifrec.osaka-u.ac.jp/www/
• [Remarks] 改正研究室 研究業績2013，2014年
  • URL: http://www.wakayama-med.ac.jp/med/seitai/
• [Remarks] 自然炎症―内因性リガンドによって誘導される自然炎症の分子基盤とその破綻
  • URL: http://shizen-enshow.jp/