Development of Inhibitory method specific for activated T cells

• Project/Area Number: 17K19576
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Pathology, Infection/Immunology, and related fields
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Saito Takashi 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 (50205655)
• Project Period (FY): 2017-06-30 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: STING / T細胞 / 増殖抑制 / 活性化シグナル / mTORC1 / IFN-g / 活性化抑制 / mTOR / cGAMP / 免疫抑制剤

Outline of Final Research Achievements

Aberrantly activated T cells induce autoimmune and allergic diseases. So far, all immunosuppressive drugs work on all T cells, and the method to specifically inhibit activated T cells is desired. When T cells were stimulated with STING ligand, cGAMP together with antigen, growth inhibition was induced only on activated T cells. cGAMP stimulation induces inhibition of mTOR activation, leading to growth inhibition of T cells. On the other hand, cGAMP stimulation induces positively type I-IFN from T cells. Direct stimulation of T cells by cGAMP innoculation in vivo augments of anti-tumor immunity

Academic Significance and Societal Importance of the Research Achievements

特異抗原で活性化されたT細胞を特異的に抑制する方法はこれまでなかったが、少なくともin vitroでは、活性化T細胞を抗原とともにSTINGを共刺激すれば、特異的なT細胞増殖抑制が誘導されることがわかり、自己免疫疾患やアレルギーなど異常に活性化されたT細胞を抑制できる方法開発の端緒についた。一方同時にSTING刺激でT細胞から自然免疫を凌ぐ大量なI型IFNが産生され、in vivo投与によってcGAMPは抗腫瘍活性を亢進できることが判明し、I型IFNによる制御に新しい局面を開いた。

Research Products

• [Journal Article] T cell co-stimulation and functional modulation by innate signals (2020)
  • Author(s): Imanishi T. and Saito T.
  • Journal Title: Trends Immunol Volume: 41 Issue: 3 Pages: 200-212
  • DOI: 10.1016/j.it.2020.01.003
  • Peer Reviewed
• [Journal Article] Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function (2019)
  • Author(s): Imanishi Takayuki、Unno Midori、Kobayashi Wakana、Yoneda Natsumi、Matsuda Satoshi、Ikeda Kazutaka、Hoshii Takayuki、Hirao Atsushi、Miyake Kensuke、Barber Glen N、Arita Makoto、Ishii Ken J、Akira Shizuo、Saito Takashi
  • Journal Title: Life Science Alliance Volume: 2 Issue: 1 Pages: e201800282-e201800282
  • DOI: 10.26508/lsa.201800282
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular dynamics of co-signal molecules in T cell activation (2019)
  • Author(s): Saito T.
  • Journal Title: Adv. Exp. Med. Biol. Volume: 1189 Pages: 135-142
  • DOI: 10.1007/978-981-32-9717-3_5
  • ISBN: 9789813297166, 9789813297173
  • Peer Reviewed
• [Journal Article] Importance of Fc Receptor γ-Chain ITAM Tyrosines in Neutrophil Activation and in vivo Autoimmune Arthritis (2019)
  • Author(s): Nemeth T, Futosi K., Szabo M., Aradi P., Saito T., Mocsai A. and Jakus Z
  • Journal Title: Frontiers in Immunology Volume: 10 Pages: 252-252
  • DOI: 10.3389/fimmu.2019.00252
  • 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] A unique nanoparticulate TLR9 agonist enables a HA split vaccine to confer FcγR-mediated protection against heterologous lethal influenza virus infection (2018)
  • Author(s): Yamamoto Takuya、Masuta Yuji、Momota Masatoshi、Kanekiyo Masaru、Kanuma Tomohiro、Takahama Shoukichi、Moriishi Eiko、Yasutomi Yasuhiro、Saito Takashi、Graham Barney S、Takahashi Yoshimasa、Ishii Ken J
  • Journal Title: International Immunology Volume: 31 Issue: 2 Pages: 81-90
  • DOI: 10.1093/intimm/dxy069
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Advax, a Delta Inulin Microparticle, Potentiates In-built Adjuvant Property of Co-administered Vaccines (2017)
  • Author(s): Hayashi Masayuki、Aoshi Taiki、Haseda Yasunari、Kobiyama Kouji、Wijaya Edward、Nakatsu Noriyuki、Igarashi Yoshinobu、Standley Daron M.、Yamada Hiroshi、Honda-Okubo Yoshikazu、Hara Hiromitsu、Saito Takashi、Takai Toshiyuki、Coban Cevayir、Petrovsky Nikolai、Ishii Ken J.
  • Journal Title: EBioMedicine Volume: 15 Pages: 127-136
  • DOI: 10.1016/j.ebiom.2016.11.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Analyzing the Dynamics of Signaling Microclusters (2017)
  • Author(s): Hashimoto-Tane A, Yokosuka T, Saito T.
  • Journal Title: The Immune Synapse Volume: 1584 Pages: 5-64
  • DOI: 10.1007/978-1-4939-6881-7_4
  • ISBN: 9781493968794, 9781493968817
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CD4 CTL, a Cytotoxic Subset of CD4+ T Cells, Their Differentiation and Function (2017)
  • Author(s): Takeuchi Arata、Saito Takashi
  • Journal Title: Frontiers in Immunology Volume: 8 Pages: 194-194
  • DOI: 10.3389/fimmu.2017.00194
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Negative regulation of T cell activation and function by the CINB5 adaptor protein (2019)
  • Author(s): Saito T., Hashimoto-Tane A., Kong M.S.
  • Organizer: FASEB Science Research Conference
  • Int'l Joint Research / Invited
• [Presentation] mTORC1 signals control TLR2 pathways in T cells by inducing TIRAP expression (2019)
  • Author(s): Imanishi T. and Saito T.
  • Organizer: The 48th Annual Meeting of the Japanese Society for Immunology
• [Presentation] Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and functions (2018)
  • Author(s): Takayuki Imanishi, Takashi Saito
  • Organizer: TOLL Meeting 2018
  • Int'l Joint Research
• [Presentation] Molecular assembly and function of PTPN22 in T cell receptor signaling (2018)
  • Author(s): Akiko Hashimoto-Tane, Takashi Saito
  • Organizer: FASEB Immunoreceptors and Immunotherapy
  • Int'l Joint Research
• [Presentation] Dynamic regulation of inhibitory signals on T cell activation (2018)
  • Author(s): Takashi Saito
  • Organizer: EMBO Workshop: Lymphocyte antigen receptor signalling
  • Int'l Joint Research
• [Presentation] Negative regulation of T cell activation and function by the CINB5 adaptor protein (2018)
  • Author(s): Takashi Saito, Mei Suen Kong, Akiko Hashimoto-Tane
  • Organizer: The 47th Annual Meeting of the Japanese Society for Immunology
• [Presentation] Functional analysis of autoimmune-associated phosphatase PTPN2(TCPTP) in T cells (2018)
  • Author(s): Akiko Hashimoto-Tane, Takashi Saito
  • Organizer: The 47th Annual Meeting of the Japanese Society for Immunology
• [Presentation] Reciprocal regulation of STING and TCR signaling by mTORC1 for T cell activation and functions (2018)
  • Author(s): Takayuki Imanishi, Takashi Saito
  • Organizer: The 47th Annual Meeting of the Japanese Society for Immunology
• [Presentation] Dynamic negative regulation of T cell activation by co-inhibitory receptor and adaptors (2018)
  • Author(s): Takashi Saito
  • Organizer: Seminar in Hokkaido University
  • Invited
• [Presentation] STING activation induces inhibition of cell growth and production of type-I IFN (2018)
  • Author(s): Takayuki Imanishi, Takashi Saito
  • Organizer: Keystone Symposia Conference T Cell Dysfunction, Cancer and Infection
  • Int'l Joint Research
• [Presentation] Regulation of T cell activation and function by innate signals -STING activation in T cells induce growth arrest and IFN production (2017)
  • Author(s): Takayuki Imanishi, Takashi Saito
  • Organizer: FASEB Summer Research conference: Signal Transduction in the Immune System
  • Int'l Joint Research
• [Presentation] Regulation of T cell activation and function by innate signals - STING activation induce growth arrest and IFN production in T cells - (2017)
  • Author(s): Takashi Saito
  • Organizer: 大阪大学 IFReC Colloquium
• [Presentation] Molecular assembly and function of PTPN22 in T cell receptor signaling (2017)
  • Author(s): Akiko Hashimoto-Tane, Takashi Saito
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] TCR-signals control STING-mediated type 1 IFN responses in T cells (2017)
  • Author(s): Takayuki Imanishi, Takashi Saito
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Regulation of T cell activation and function by innate signals (2017)
  • Author(s): Takashi Saito
  • Organizer: Seminar in Hokkaido University
  • Invited
• [Patent(Industrial Property Rights)] 免疫細胞の制御技術 (2017)
  • Inventor(s): Takashi Saito, Takayuki Imanishi
  • Industrial Property Rights Holder: Takashi Saito, Takayuki Imanishi
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017