Inhibitory mechanism of T cell function by inhibitory receptors

• Project/Area Number: 18H02672
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• 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): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: T細胞 / 抑制性レセプター / ミクロクラスター / PD-1 / チェックポイント阻害剤 / LAG-3 / TIGIT / 活性化シグナル / T細胞活性化 / TCRミクロクラスター / LAG3 / イメージング解析 / 抑制機能

Outline of Final Research Achievements

T cells are dysfunction in chronic infection and cancer. This dysfunction is induced by inhibitory signals through inhibitory receptors as PD-1. This study analyzed inhibitory mechanism of T cell activation and function by such inhibitory receptor LAG-3. LAG-3 induced cluster formation upon T cell activation which are co-localized with TCR-microclusters. LAG-3-mediated inhibition of T cell activation depends on cytoplasmic region of LAG-3, but the cluster formation did not require the cytoplasmic region. While anti-LAG-3 augmented T cell activation, bi-specific Ab against LAG-3 and PD-1 induced stronger activation. Analysis of inhibitory anti-LAG-3 Abs, it was suggested that inhibitory function of LAG-3 do not require MHC-II association but do need assembly with the TCR complex.

Academic Significance and Societal Importance of the Research Achievements

がんに対するチェックポイント療法が大きく進み、より良い療法が期待されている。PD-1やCTLA-4以外の抑制性受容体の制御によって疲弊T細胞を活性化が示唆されている。その代表の抑制受容体LAG-3を介したT細胞機能の抑制メカニズムを明らかにすることは、PD-1との異同を含めて、学術的に極めて重要であり、実際に臨床で使用するためにLAG-3の機能機作の解明は必須である。また、今回PD-1とLAG-3のbi-specific抗体についても解析したが、実際にこのbi-specific抗体が、現状のPD-1抗体に替わる日は遠くないと思われ、その基本的性状の解析もまた大変意義のあることである。

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] mTORC1 Signaling Controls TLR2-Mediated T-Cell Activation by Inducing TIRAP Expression (2020)
  • Author(s): Imanishi Takayuki、Unno Midori、Kobayashi Wakana、Yoneda Natsumi、Akira Shizuo、Saito Takashi
  • Journal Title: Cell Reports Volume: 32 Issue: 3 Pages: 107911-107911
  • DOI: 10.1016/j.celrep.2020.107911
  • Peer Reviewed / Open Access
• [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] 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] 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] 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
• [Presentation] Regulation of T cell function by innate immune signals (2020)
  • Author(s): Imanishi Takayuki、Saito Takashi
  • Organizer: 14th World Immune Regulation Meeting
  • Int'l Joint Research
• [Presentation] Regulation of cell adhesion and activation at Immune synapse (2020)
  • Author(s): Saito Takashi
  • Organizer: The 43rd Annual Meeting of the Molecular Biology Society of Japan
  • 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] 自己免疫関連脱リン酸化酵素PTPN22がT細胞活性化に伴って形成する抑制性コンプレックスの解析 (2019)
  • Author(s): Hashimoto-Tane A. and Saito T.
  • Organizer: 第29 回学術集会 Kyoto T Cell Conference
• [Presentation] T細胞受容体クラスターとPTPN22(Lyp)を含む自己免疫関連分子集合体の解析 (2019)
  • Author(s): Hashimoto-Tane A. and Saito T.
  • Organizer: 第140回日本薬理学会関東部会
• [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