Development of a novel method to study immune memory

• Project/Area Number: 18K19447
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: Osaka University
• Principal Investigator: Kurosaki Tomohiro 大阪大学, 免疫学フロンティア研究センター, 特任教授(常勤) (50178125)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2018: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: ケミカルジェネティクス / 時空間的制御 / PI3キナーゼ / mTORC1 / rapamycin / 変異mTORC1 / 時空間制御 / 可逆的阻害 / メモリーB細胞

Outline of Final Research Achievements

Development of a new method to reversibly inactivate specific genes in a tempo-spatial way is very important for biological research. Here, we have tried to develop a experimental system to reversibly inactivate the mTOC1 molecule in the B cell specific manner during a certain time window. To do this, we found that cells expressing the mutant mTORC1, being resistant to rapamycin, indeed behaved independently of rapamycin treatment. Then, we will intend to establish the transgenic mice expressing the resistant mTORC1 except B lineage cells, which allow us to inhibit mTORC1 in a B cell specific manner by rapamycin.

Academic Significance and Societal Importance of the Research Achievements

私たちは、多くの薬剤を用いて疾病の予防・治療を行っているわけであるが、実際、その薬剤は、「どの細胞のいつの時期」効いて、薬効を発現しているのかは明白にされていない。この研究で樹立された、特定の細胞のみで薬効が働く、方法は、この疑問解決に大変重要なツールを与えることになる。又、本研究からの重要な進展は、薬剤ターゲットを変異して、この変異ターゲットのみに働く薬剤の開発を同時に行うことにより、ある特定の細胞（例えば癌細胞）のみに働く薬剤を生体に投与し、正常細胞への影響を殆どなくすことも可能になる。

Research Products

• [Journal Article] Repurposing the psoriasis drug Oxarol to an ointment adjuvant for the influenza vaccine (2020)
  • Author(s): Sato Ryota、Makino-Okamura Chieko、Lin Quingshun、Wang Muying、Shoemaker Jason E、Kurosaki Tomohiro、Fukuyama Hidehiro
  • Journal Title: International Immunology Volume: - Issue: 8 Pages: 499-507
  • DOI: 10.1093/intimm/dxaa012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Restricted Clonality and Limited Germinal Center Reentry Characterize Memory B Cell Reactivation by Boosting (2020)
  • Author(s): Mesin Luka、Schiepers Arien、Ersching Jonatan、Barbulescu Alexandru、Cavazzoni Cecilia B.、Angelini Alessandro、Okada Takaharu、Kurosaki Tomohiro、Victora Gabriel D.
  • Journal Title: Cell Volume: 180 Issue: 1 Pages: 92-106
  • DOI: 10.1016/j.cell.2019.11.032
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity (2020)
  • Author(s): Tanaka S, Ise W, Inoue T,Ito A, Ono C, Shima Y, Sakakibara S, Nakayama M, Fujii K, Miura I,Sharif J, Koseki H, Pandelakis K, Raman I, Li Q,Kubo M, Fujiki K, Nakato R, Shirahige K, Araki H, Miura F, Ito T,Kawakami E, Baba Y, and Kurosaki T.
  • Journal Title: Nature Immunology Volume: -
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis (2020)
  • Author(s): Sidwell Tom、Liao Yang、Garnham Alexandra L.、Vasanthakumar Ajithkumar、Gloury Renee、Blume Jonas、Teh Peggy P.、Chisanga David、Thelemann Christoph、de Labastida Rivera Fabian、Engwerda Christian R.、Corcoran Lynn、Kometani Kohei、Kurosaki Tomohiro、Smyth Gordon K.、Shi Wei、Kallies Axel
  • Journal Title: Nature Communications Volume: 11 Issue: 1
  • DOI: 10.1038/s41467-019-14112-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] B cell‐intrinsic MyD88 signaling controls IFN‐γ‐mediated early IgG2c class switching in mice in response to a particulate adjuvant (2019)
  • Author(s): Lee Michelle Sue Jann、Natsume‐Kitatani Yayoi、Temizoz Burcu、Fujita Yukiko、Konishi Aki、Matsuda Kyoko、Igari Yoshikatsu、Tsukui Toshihiro、Kobiyama Kouji、Kuroda Etsushi、Onishi Motoyasu、Marichal Thomas、Ise Wataru、Inoue Takeshi、Kurosaki Tomohiro、Mizuguchi Kenji、Akira Shizuo、Ishii Ken J、Coban Cevayir
  • Journal Title: European Journal of Immunology Volume: 49 Issue: 9 Pages: 1433-1440
  • DOI: 10.1002/eji.201848084
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Requirement for memory B-cell activation in protection from heterologous influenza virus reinfection (2019)
  • Author(s): Leach Sarah、Shinnakasu Ryo、Adachi Yu、Momota Masatoshi、Makino-Okamura Chieko、Yamamoto Takuya、Ishii Ken J、Fukuyama Hidehiro、Takahashi Yoshimasa、Kurosaki Tomohiro
  • Journal Title: International Immunology Volume: 31 Issue: 12 Pages: 771-779
  • DOI: 10.1093/intimm/dxz049
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Exposure of an occluded hemagglutinin epitope drives selection of a class of cross-protective influenza antibodies (2019)
  • Author(s): Adachi Yu、Tonouchi Keisuke、Nithichanon Arnone、Kuraoka Masayuki、Watanabe Akiko、Shinnakasu Ryo、Asanuma Hideki、Ainai Akira、Ohmi Yusuke、Yamamoto Takuya、Ishii Ken J.、Hasegawa Hideki、Takeyama Haruko、Lertmemongkolchai Ganjana、Kurosaki Tomohiro、Ato Manabu、Kelsoe Garnett、Takahashi Yoshimasa
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1-13
  • DOI: 10.1038/s41467-019-11821-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] GPR40 activation initiates store-operated Ca2+ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells (2019)
  • Author(s): Usui R, Yabe D, Fauzi M, Goto H, Botagarova A, Tokumoto S, Tatsuoka H, Tahara Y, Kobayashi S, Manebe T, Baba Y, Kurosaki T, Herrera PL, Ogura M, Nagashima K, Inagaki N
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 15562-15562
  • DOI: 10.1038/s41598-019-52048-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition) (2019)
  • Author(s): Cossarizza A,…150 authors…,Wing, JB….16 authors… Zychlinsky A
  • Journal Title: European Journal of Immunology Volume: 49 Issue: 10 Pages: 1457-1973
  • DOI: 10.1002/eji.201970107
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Plasma cell differentiation during the germinal center reaction (2019)
  • Author(s): Ise Wataru、Kurosaki Tomohiro
  • Journal Title: Immunological Reviews Volume: 288 Issue: 1 Pages: 64-74
  • DOI: 10.1111/imr.12751
  • Peer Reviewed
• [Journal Article] Inhibition of T cell activation and function by the adaptor protein CIN85. (2019)
  • Author(s): Kong Mei S*., Hashimoto-Tane A*., Kawashima Y., Sakuma M., Yokosuka T., Kometani K., Onishi R., Carpino N., Ohara O., Kurosaki T., Phua K.K. and Saito, T.
  • Journal Title: Science Signaling Volume: 12 Issue: 567 Pages: 1609-1625
  • DOI: 10.1126/scisignal.aav4373
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] KLRG1+ effector CD8+ T cells lose KLRG1, differentiate into all memory T cell lineages, and convey enhanced protective immunity (2018)
  • Author(s): Dietmar Herndler-Brandstetter, Harumichi Ishigame, Ryo Shinnakasu, Valerie Plajer, Carmen Stecher, Jun Zhao, Melanie Lietzenmayer, Lina Kroehling, Akiko Takumi, Kohei Kometani, Takeshi Inoue, Yuval Kluger, Susan M. Kaech, Tomohiro Kurosaki, Takaharu Okada & Richard A. Flavell
  • Journal Title: Immunity Volume: 48(4) Issue: 4 Pages: 716-729
  • DOI: 10.1016/j.immuni.2018.03.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Generation of memory B cells and their reactivation. (2018)
  • Author(s): Inoue T, Moran I, Shinnakasu R, Phan TG, Kurosaki T.
  • Journal Title: Immunological Reviews Volume: 283(1) Issue: 1 Pages: 138-149
  • DOI: 10.1111/imr.12640
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] T Follicular Helper Cell-Germinal Center B Cell Interaction Strength Regulates Entry into Plasma Cell or Recycling Germinal Center Cell Fate (2018)
  • Author(s): Ise Wataru、Fujii Kentaro、Shiroguchi Katsuyuki、Ito Ayako、Kometani Kohei、Takeda Kiyoshi、Kawakami Eiryo、Yamashita Kazuo、Suzuki Kazuhiro、Okada Takaharu、Kurosaki Tomohiro
  • Journal Title: Immunity Volume: 48 Issue: 4 Pages: 702-715
  • DOI: 10.1016/j.immuni.2018.03.027
  • Peer Reviewed / Open Access
• [Journal Article] The adaptor molecule CD2AP in CD4 T cells modulates differentiation of follicular helper T cells during chronic LCMV infection (2018)
  • Author(s): Raju Saravanan、Kometani Kohei、Kurosaki Tomohiro、Shaw Andrey S.、Egawa Takeshi
  • Journal Title: PLOS Pathogens Volume: 14 Issue: 5 Pages: e1007053-e1007053
  • DOI: 10.1371/journal.ppat.1007053
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] R-Ras2 is required for germinal center formation to aid B cells during energetically demanding processes (2018)
  • Author(s): Mendoza Pilar、Martinez-Martin Nuria、Bovolenta Elena R.、Reyes-Garau Diana、Hernansanz-Agustin Pablo、Delgado Pilar、 Diaz-Munoz Manuel D.、Oeste Clara L.、Fernandez-Pisonero Isabel、Castellano Ester、Martinez-Ruiz Antonio、 Alonso-Lopez Diego、Santos Eugenio、Bustelo Xose R.、Kurosaki Tomohiro、Alarcon Balbino
  • Journal Title: Science Signaling Volume: 11 Issue: 532
  • DOI: 10.1126/scisignal.aal1506
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles. (2018)
  • Author(s): Kayama H, Kohyama M, Okuzaki D, Motooka D, Barman S, Okumura R, Muneta M, Hoshino K, Sasaki I, Ise W, Matsuno H, Nishimura J, Kurosaki T, Nakamura S, Arase H, Kaisho T, Takeda K.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 115 Issue: 33 Pages: 8418-8423
  • DOI: 10.1073/pnas.1808426115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Trim33 mediates the proinflammatory function of Th17 cells (2018)
  • Author(s): Tanaka Shinya、Jiang Yu、Martinez Gustavo J.、Tanaka Kentaro、Yan Xiaowei、Kurosaki Tomohiro、Kaartinen Vesa、Feng Xin-Hua、Tian Qiang、Wang Xiaohu、Dong Chen
  • Journal Title: The Journal of Experimental Medicine Volume: 215 Issue: 7 Pages: 1853-1868
  • DOI: 10.1084/jem.20170779
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Role of BACH2 in T Cells in Experimental Malaria Caused by Plasmodium chabaudi chabaudi AS (2018)
  • Author(s): Edwards Chelsea L.、de Oca Marcela Montes、de Labastida Rivera Fabian、Kumar Rajiv、Ng Susanna S.、Wang Yulin、Amante Fiona H.、Kometani Kohei、Kurosaki Tomohiro、Sidwell Tom、Kallies Axel、Engwerda Christian R.
  • Journal Title: Frontiers in Immunology Volume: 9 Pages: 2578-2578
  • DOI: 10.3389/fimmu.2018.02578
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Function of humoral memory compartments and their generation mechanism (2020)
  • Author(s): Kurosaki, T
  • Organizer: New Horizons in B Cell Biology
  • Int'l Joint Research / Invited
• [Presentation] Two functional humoral memory compartments and their generation mechanism (2020)
  • Author(s): Kurosaki, T
  • Organizer: B Cell Renaissance: Epigenetics, Regulation and Immunotherapy,Keystone Symposia
  • Int'l Joint Research / Invited
• [Presentation] Generation of humoral memory compartments (2019)
  • Author(s): Kurosaki, T.
  • Organizer: The 10th JSH INTERNATIONAL SYMPOSIUM 2019 in Ise-Shima
  • Int'l Joint Research / Invited
• [Presentation] Roles of epigenetic modification in B cell tolerance (2019)
  • Author(s): Kurosaki, T.
  • Organizer: 2nd International Symposium on B cell responses in immunity and autoimmunity
  • Int'l Joint Research / Invited
• [Presentation] 「B細胞・抗体を介する免疫制御」 (2019)
  • Author(s): 黒崎 知博
  • Organizer: 第55回日本移植学会総会
  • Invited
• [Presentation] Function of Tet proteins in B cell tolerance (2019)
  • Author(s): Kurosaki, T
  • Organizer: the International Symposium of Korean Autoimmunity-Synovitis Study Group
  • Int'l Joint Research / Invited
• [Presentation] Selection Mechanisms of Germinal Center Cells into the Memory B Cell Compartment (2019)
  • Author(s): Kurosaki, T
  • Organizer: B Cell-T Cell Interactions, Keystone Symposia Conference
  • Int'l Joint Research / Invited
• [Presentation] Bリンパ球運命決定機構 (2018)
  • Author(s): 黒崎知博
  • Organizer: 国立感染症研究所 セミナー
  • Invited
• [Presentation] Bリンパ球運命決定機構 (2018)
  • Author(s): 黒崎知博
  • Organizer: 順天堂大学 セミナー
  • Invited
• [Presentation] Fate decision of germinal center B cells (2018)
  • Author(s): Kurosaki, T
  • Organizer: B Cells: Mechanisms in Immunity and Autoimmunity Keystone Symposia Conference
  • Int'l Joint Research / Invited
• [Presentation] 液性免疫記憶生成機構 (2018)
  • Author(s): 黒崎知博
  • Organizer: 免疫サマースクール
  • Int'l Joint Research / Invited
• [Presentation] Fate decision of germinal center B cells (2018)
  • Author(s): Kurosaki, T
  • Organizer: Japanese-German Immunology Workshop
  • Int'l Joint Research / Invited
• [Presentation] Two humoral memory compartments: How are they generated? (2018)
  • Author(s): Kurosaki, T
  • Organizer: Universidad Autonoma de Madrid | UAM Seminar
  • Invited
• [Presentation] Regulation of B cell tolerance by epigenetic factors (2018)
  • Author(s): Kurosaki, T
  • Organizer: Cluster Science Days 2018 and the 10th international symposium of IFReC
  • Int'l Joint Research / Invited
• [Presentation] Fate decision of germinal center B cells (2018)
  • Author(s): Kurosaki, T
  • Organizer: International Symposium on B cells
  • Int'l Joint Research / Invited
• [Remarks] Laboratory of Lymphocyte Differentiation
  • URL: http://lymph.ifrec.osaka-u.ac.jp/
• [Remarks] http://lymph.ifrec.osaka-u.ac.jp/