Mechanism that iIntegrates neo-self antigen recognition into cell differentiation.

• Project Area: Creation, function and structure of neo-self
• Project/Area Number: 17H05805
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: 谷内 一郎 国立研究開発法人理化学研究所, 生命医科学研究センター, チームリーダー (20284573)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2018: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: 抗原認識 / T細胞 / TCR信号 / 転写因子 / 免疫学 / 細胞分化 / 核内制御 / TCRシグナル

Outline of Annual Research Achievements

当該新学術領域ネオ・セルフでは新たな抗原提示形態を介した抗原認識が関与する免疫応答のメカニズムを多角的な視点で解明することを中心課題に据えている。本研究は、ネオ・セルフ抗原認識に伴うTCR信号の変化が如何に病的なT細胞分化に繋がるか理解することを目的に、ヘルパー/キラー系列決定を制御する核内機構をモデルに、Thpok遺伝子座内のThpokサイレンサー上で起こる分子応答の解明を目指した研究を行った。Thpokサイレンサー領域の機能制御にはBcl11b転写因子のC末端のZn-finger領域が重要であることを解明したことから、本研究では以下の2項目を設定し、研究を実施した。
1. Bcl11b転写因子と会合する分子の同定とBcl11b翻訳後修飾の生理的意義の解析.
2. Site-specific ChIP法の応用によるThpokサイレンサー上の制御分子の同定.
1についてはBirA酵素により生体内でBcl11bタンパクをビオチン化する実験系を構築し、野生型とC末端Zn-finger領域を欠損する変異型Bcl11bに会合する分子の網羅的同定と比較により、C末端Zn-finger領域を介してBcl11bと会合する候補分子群を同定した。またBcl11b翻訳後修飾の生理的意義について、TCR信号下流でリン酸化されるBcl11bタンパク内の24残基のセリン/スレオニン残基のうち23残基をアラニンに置換した変異マウスを作製し解析を行った結果、リン酸化はBcl11bのヘルパー/キラー系列決定制御での機能において重要でない結果を得た。
2について新規実験手法として目的のゲノム領域上のタンパク質をビオチン化するOn -site BioID法の樹立を目的に基礎的な条件検討を行い、遊離のBirAタンパクによる非特異的なビオチン化を減弱させることが必要である結果から、今後の改良の方向性が明らかとなった.

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Runx/Cbfβ complexes protect group 2 innate lymphoid cells from exhausted-like hyporesponsiveness during allergic airway inflammation (2019)
  • Author(s): Miyamoto Chizuko、Kojo Satoshi、Yamashita Motoi、Moro Kazuyo、Lacaud Georges、Shiroguchi Katsuyuki、Taniuchi Ichiro、Ebihara Takashi
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 447-447
  • DOI: 10.1038/s41467-019-08365-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differential Requirement of Cd8 Enhancers E8I and E8VI in Cytotoxic Lineage T Cells and in Intestinal Intraepithelial Lymphocytes (2019)
  • Author(s): Gulich Alexandra Franziska、Preglej Teresa、Hamminger Patricia、Alteneder Marlis、Tizian Caroline、Orola Maria Jonah、Muroi Sawako、Taniuchi Ichiro、Ellmeier Wilfried、Sakaguchi Shinya
  • Journal Title: Frontiers in Immunology Volume: 10
  • DOI: 10.3389/fimmu.2019.00409
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Runx-dependent and silencer-independent repression of a maturation enhancer in the Cd4 gene (2018)
  • Author(s): Kojo Satoshi、Yasmin Nighat、Muroi Sawako、Tenno Mari、Taniuchi Ichiro
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 3593-3593
  • DOI: 10.1038/s41467-018-05803-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tle corepressors are differentially partitioned to instruct CD8+ T cell lineage choice and identity (2018)
  • Author(s): Xing Shaojun、Shao Peng、Li Fengyin、Zhao Xudong、Seo Wooseok、Wheat Justin C.、Ramasamy Selvi、Wang Jianfeng、Li Xiang、Peng Weiqun、Yu Shuyang、Liu Chengyu、Taniuchi Ichiro、Sweetser David A.、Xue Hai-Hui
  • Journal Title: The Journal of Experimental Medicine Volume: 215 Issue: 8 Pages: 2211-2226
  • DOI: 10.1084/jem.20171514
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CD4 Helper and CD8 Cytotoxic T Cell Differentiation (2018)
  • Author(s): Taniuchi Ichiro
  • Journal Title: Annual Review of Immunology Volume: 36 Issue: 1 Pages: 579-601
  • DOI: 10.1146/annurev-immunol-042617-053411
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cbfβ2 controls differentiation of and confers homing capacity to prethymic progenitors (2018)
  • Author(s): Tenno Mari、Kojo Satoshi、Lawir Divine-Fondzenyuy、Hess Isabell、Shiroguchi Katsuyuki、Ebihara Takashi、Endo Takaho A.、Muroi Sawako、Satoh Rumi、Kawamoto Hiroshi、Boehm Thomas、Taniuchi Ichiro
  • Journal Title: J. Exp. Med Volume: 215 Issue: 2 Pages: 595-610
  • DOI: 10.1084/jem.20171221
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Requirement for intron structures in activating theCd8alocus (2018)
  • Author(s): Wada Hisashi、Yasmin Nighat、Kakugawa Kiyokazu、Ohno-Oishi Michiko、Nieke Sebastian、Miyamoto Chizuko、Muroi Sawako、Taniuchi Ichiro
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 115 Issue: 13 Pages: 3440-3445
  • DOI: 10.1073/pnas.1718837115
  • Peer Reviewed
• [Journal Article] Unique N-terminal sequences in two Runx1 isoforms are dispensable for Runx1 function (2017)
  • Author(s): Nieke Sebastian、Yasmin Nighat、Kakugawa Kiyokazu、Yokomizo Tomomasa、Muroi Sawako、Taniuchi Ichiro
  • Journal Title: BMC Dev Biol Volume: 17 Issue: 1 Pages: 14-14
  • DOI: 10.1186/s12861-017-0156-y
  • Peer Reviewed / Open Access
• [Journal Article] Priming of lineage-specifying genes by Bcl11b is required for lineage choice in post-selection thymocytes. (2017)
  • Author(s): Kojo S, Tanaka H, Endo TA, Muroi S, Liu Y, Seo W, Tenno M, Kakugawa K, Naoe Y, Nair K, Moro K, Katsuragi Y, Kanai A, Inaba T, Egawa T, Venkatesh B, Minoda A, Kominami R, Taniuchi I.
  • Journal Title: Nat Commun. Volume: 8 Issue: 1 Pages: 702-702
  • DOI: 10.1038/s41467-017-00768-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cbfβ2 deficiency preserves Langerhans cell precursors by lack of selective TGFβ receptor signaling (2017)
  • Author(s): Tenno Mari、Shiroguchi Katsuyuki、Muroi Sawako、Kawakami Eiryo、Koseki Keita、Kryukov Kirill、Imanishi Tadashi、Ginhoux Florent、Taniuchi Ichiro
  • Journal Title: The Journal of Experimental Medicine Volume: 214 Issue: 10 Pages: 2933-2946
  • DOI: 10.1084/jem.20170729
  • Peer Reviewed / Open Access
• [Journal Article] Runx1 mediates the development of the granular convoluted tubules in the submandibular glands (2017)
  • Author(s): Ono Minagi Hitomi、Sarper Safiye Esra、Kurosaka Hiroshi、Kuremoto Koh-ichi、Taniuchi Ichiro、Sakai Takayoshi、Yamashiro Takashi
  • Journal Title: PLOS ONE Volume: 12 Issue: 9 Pages: 0184395-0184395
  • DOI: 10.1371/journal.pone.0184395
  • Peer Reviewed / Open Access
• [Journal Article] The transcription factor Runx3 guards cytotoxic CD8+ effector T cells against deviation towards follicular helper T cell lineage (2017)
  • Author(s): Shan Qiang、Zeng Zhouhao、Xing Shaojun、Li Fengyin、Hartwig Stacey M、Gullicksrud Jodi A、Kurup Samarchith P、Van Braeckel-Budimir Natalija、Su Yao、Martin Matthew D、Varga Steven M、Taniuchi Ichiro、Harty John T、Peng Weiqun、Badovinac Vladimir P、Xue Hai-Hui
  • Journal Title: Nat. Immunol Volume: 18 Issue: 8 Pages: 931-939
  • DOI: 10.1038/ni.3773
  • Peer Reviewed
• [Journal Article] Essential Roles of SATB1 in Specifying T Lymphocyte Subsets (2017)
  • Author(s): Kakugawa Kiyokazu、Kojo Satoshi、Tanaka Hirokazu、Seo Wooseok、Endo Takaho A.、Kitagawa Yohko、Muroi Sawako、Tenno Mari、Yasmin Nighat、Kohwi Yoshinori、Sakaguchi Shimon、Kowhi-Shigematsu Terumi、Taniuchi Ichiro
  • Journal Title: Cell Rep Volume: 19 Issue: 6 Pages: 1176-1188
  • DOI: 10.1016/j.celrep.2017.04.038
  • NAID: 40021496454
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distinct requirement of Runx complexes for TCRβ enhancer activation at distinct developmental stages. (2017)
  • Author(s): Seo W, Muroi S, Akiyama K and Taniuchi I.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 41351-41351
  • DOI: 10.1038/srep41351
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment. (2017)
  • Author(s): Kitagawa Y, Ohkura N, Kidani Y, Vandenbon A, Hirota K, Kawakami R, Yasuda K, Motooka D, Nakamura S, Kondo M, Taniuchi I, Kohwi-Shigematsu T, Sakaguchi S.
  • Journal Title: Nat Immunol. Volume: 18(2) Issue: 2 Pages: 173-183
  • DOI: 10.1038/ni.3646
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Roles of RUNX Complexes in Immune Cell Development (2017)
  • Author(s): Ebihara T., Seo W., Taniuchi I.
  • Journal Title: Advances in Experimental Medicine and Biology Volume: 962 Pages: 395-413
  • DOI: 10.1007/978-981-10-3233-2_24
  • ISBN: 9789811032318, 9789811032332
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Gene regulation by local and long-range chromatin loops during CD4/CD8 lineage choice (2019)
  • Author(s): Ichiro Taniuchi
  • Organizer: The Keystone Symposia
  • Int'l Joint Research / Invited
• [Presentation] Regulation of Dendritic Cell Development by Runx Factors (2018)
  • Author(s): Ichiro Taniuchi
  • Organizer: The 1st International Symposium on NEO-SELF
  • Int'l Joint Research / Invited
• [Presentation] 皮膚免疫細胞の分化過程におけるRunx 転写因子の働き (2018)
  • Author(s): Ichiro Taniuchi
  • Organizer: 第67 回 日本アレルギー学会
  • Invited
• [Presentation] Unraveling pathogenesis of human primary immune deficiency by mouse models (2018)
  • Author(s): Ichiro Taniuchi
  • Organizer: The 6th Kyoto Course on Bioinformatics for Genomic Medicine International Symposium on Disease Genomics.
  • Int'l Joint Research / Invited
• [Presentation] Roles of Runx Transcription Factors in Immune Cell Development (2017)
  • Author(s): Ichiro Taniuchi
  • Organizer: The 46th JSI annual meeting,
  • Int'l Joint Research / Invited
• [Presentation] Unique roles of the C-terminal end sequences in Runx and Cbfb proteins (2017)
  • Author(s): Ichiro Taniuchi
  • Organizer: The 21st International RUNX Conference
  • Int'l Joint Research / Invited
• [Presentation] Roles of Runx Transcription Factors in Immune System Development (2017)
  • Author(s): Ichiro Taniuchi
  • Organizer: IMS-JSI International Symposium on Immunology 2017
  • Int'l Joint Research / Invited
• [Presentation] Regulation of T cell development in the thymus by transcription factors (2017)
  • Author(s): Ichiro Taniuchi
  • Organizer: Symposium in honor of Ellen Rothenberg, The Molecular Developmental Biology of Lymphocytes
  • Int'l Joint Research / Invited
• [Presentation] 転写因子の機能制御と 免疫系の発生・分化制御 (2017)
  • Author(s): 谷内 一郎
  • Organizer: 第40回日本分子生物学会年会
  • Invited
• [Remarks] 新たなT細胞分化制御機構を発見 －Cd4サイレンサー非依存的なCd4遺伝子発現制御－
  • URL: http://www.riken.jp/pr/press/2018/20180905_1/
• [Remarks] ランゲルハンス細胞の分化機構を解明
  • URL: http://www.riken.jp/pr/press/2017/20170828_1/
• [Remarks] Laboratory for Transcriptional Regulation
  • URL: http://www.ims.riken.jp/labo/20/index.html
• [Remarks] T細胞分化を管理する転写制御機構を解明 －転写因子Bcl11bが適切なT細胞系列決定を担う－
  • URL: http://www.riken.jp/pr/press/2017/20170926_3/