T cell activation regulation upon self recognition

• Project Area: Creation, function and structure of neo-self
• Project/Area Number: 17H05806
• 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: 斉藤 隆 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): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000); Fiscal Year 2018: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
• Keywords: 自己ペプチド / T細胞 / 活性化シグナル / 自己認識 / 免疫寛容 / 樹状細胞 / 不応答 / 自己ペプチド認識 / a

Outline of Annual Research Achievements

T細胞が自己抗原の認識によって"セミ活性化状態"にある実態の解明とそれを誘導するシグナルと機序を解析することを目指した。樹状細胞（DC）を除去したマウス、又は抗MHC-II抗体を投与したマウスのT細胞は、抗原/MHC及び抗CD3/CD28抗体の刺激に対して増殖やサイトカイン産生の低応答性が誘導される。MHCII抗体を投与した、無菌マウス由来のT細胞も同様に低応答であり、不応答状態は外来抗原特に腸管内細菌由来抗原に寄らず、自己ペプチドの認識の欠如によって誘導されると思われる。自己ペプチドの認識による"セミ活性化"を誘導する活性化シグナルを解析するため、抗MHC-II抗体を投与したマウス、またはMHC-II欠損マウスに正常T細胞を移入したマウスのT細胞を取り出して、ex vivoにおける種々のシグナル分子や転写因子の活性化を解析した。その結果、自己認識が阻害されたT細胞では、TCRの下流シグナル分子である Erk, p38, S6などのリン酸化が抑制され、更にNFATc1/NFATc2の核内移行・活性化が抑制されていた。即ち、自己ペプチド認識に伴って、少なくともこれらの分子が活性化シグナルを伝達していることが判明した。また、誘導される転写因子などの遺伝子発現を調べ、Egr-1, 2, 3, Nab-2などの発現が抑制された。特にEgr-1は異なる系で抑制が示され、IL-2プロモーターに結合することが示されているため、Egr-1のT細胞での強制発現マウスを解析したところ、ナイーブT細胞では活性化によるIL-2産生が亢進することが分かった。これらの結果から、自己ペプチド認識によってT細胞に誘導される活性化シグナルの実態の一部が初めて明らかになり、活性化による機能発現の予備段階を形成していることが示唆された。

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] 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] 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] 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] Deregulated Mucosal Immune Surveillance through Gut-Associated Regulatory T Cells and PD-1+T Cells in Human Colorectal Cancer (2018)
  • Author(s): Fujimoto Hanae、Saito Yoriko、Ohuchida Kenoki、Kawakami Eiryo、Fujiki Saera、Watanabe Takashi、Ono Rintaro、Kaneko Akiko、Takagi Shinsuke、Najima Yuho、Hijikata Atsushi、Cui Lin、Ueki Takashi、Oda Yoshinao、Hori Shohei、Ohara Osamu、Nakamura Masafumi、Saito Takashi、Ishikawa Fumihiko
  • Journal Title: The Journal of Immunology Volume: 200 Issue: 9 Pages: 3291-3303
  • DOI: 10.4049/jimmunol.1701222
  • Peer Reviewed
• [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] 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] 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
  • Industrial Property Number: 2017-028244
  • Filing Date: 2017