Mechanism of T cell activation regulation by TCR microclusters and the costimulation network.

• Project/Area Number: 24590590
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Tokyo Medical University (2015); The Institute of Physical and Chemical Research (2012-2014)
• Principal Investigator: Yokosuka Tadashi 東京医科大学, 医学部, 教授 (10359599)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 免疫学 / シグナル伝達 / 分子イメージング / T細胞受容体 / 補助刺激受容体

Outline of Final Research Achievements

The imaging analysis revealed a new insight that a negative costimulatory receptor, PD-1, accumulated at a T cell signalosome, the TCR microcluster, and recruited a phosphatase, SHP2, to suppress T cell activation in a ligand-binding manner. The anti-PD-1 antibody, whose an advantage in the immune check-point therapy, blocked the aggregation of PD-1 at the TCR microclusters, resulting in the recovery of T cell activation. An activating costimulatory receptor, ICOS, increased the translocation of PI3K at TCR microclusters through the binding to its ligands. These data demonstrate that T cell activation is spatiotemporally regulated by both activating and suppressive costimulation signalosomes.

Research Products

• [Int'l Joint Research] INSERM（フランス国立保健医学研究機）(フランス)
• [Int'l Joint Research] DRFZ（ドイツリウマチセンター）(ドイツ)
• [Int'l Joint Research] ウイーン大学(オーストリア)
• [Journal Article] Differential Regulation of T-dependent and -independent Antibody Responses through Arginine Methyltransferase PRMT1 in vivo (2016)
  • Author(s): Kikumi Hata, Noriko Yanase, Katsuko Sudo, Hiroshi Kiyonari, Yoshiko Mukumoto, Junichiro Mizuguchi, Tadashi Yokosuka
  • Journal Title: FEBS Letters Volume: 590 Issue: 8 Pages: 1200-1210
  • DOI: 10.1002/1873-3468.12161
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 免疫シナプス (2015)
  • Author(s): 横須賀忠
  • Journal Title: 生体の科学 Volume: 66 Pages: 522-523
• [Journal Article] Clustering of CARMA1 through SH3-GUK domain interactions is required for its activation of NF-kB signaling (2015)
  • Author(s): Hara, H., Yokosuka, T., Hirakawa, H., Ishihara, C., Yasukawa, S., Yamazaki, M., Koseki, H., Yoshida, H. and Saito, T.
  • Journal Title: Nat. Commun. Volume: 6 Issue: 1 Pages: 5555-5555
  • DOI: 10.1038/ncomms6555
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] T細胞免疫シナプス研究の最新事情 (2015)
  • Author(s): 横須賀忠
  • Journal Title: 臨床免疫・アレルギー科 Volume: 63 Pages: 193-200
  • NAID: 40020362893
• [Journal Article] T細胞活性化におけるチェックポイント (2014)
  • Author(s): 横須賀忠
  • Journal Title: 炎症と免疫 Volume: 23 Pages: 10-20
• [Journal Article] T細胞におけるPD-1の生理機能と分子基盤 (2014)
  • Author(s): 横須賀忠
  • Journal Title: 腫瘍内科 Volume: 14 Pages: 419-426
• [Journal Article] The lymphoid lineage-specific actin-uncapping protein Rltpr is essential for costimulation via CD28 and the development of regulatory T cells (2013)
  • Author(s): Liang, Y., Cucchetti, M., Roncagalli, R., Yokosuka, T., Malzac, A., Bertosio, E., Imbert, J., Nijman, I.J., Suchanek, M., Saito, T., Wulfing, C., Malissen, B., Malissen, M.
  • Journal Title: Nat. Immunol. Volume: 14 Issue: 8 Pages: 858-866
  • DOI: 10.1038/ni.2634
  • Peer Reviewed
• [Journal Article] リンパ球に特異的なアクチン脱キャッピングタンパク質RltprはCD28を介するT細胞の活性化と制御性T細胞の分化に必須である (2013)
  • Author(s): 横須賀忠、斉藤隆、Bernard Malissen
  • Journal Title: ライフサイエンス新着論文レビュー Volume: -
• [Journal Article] Programmed cell death-1 forms negative costimulatorymicroclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2 (2012)
  • Author(s): Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tani A, Azuma M, Saito T
  • Journal Title: J Exp Med Volume: 209 Issue: 6 Pages: 935-945
  • DOI: 10.1084/jem.20112741
  • Peer Reviewed
• [Journal Article] A motif in the V3 domain of the kinase PKC-θ determines its localization in the immunological synapse and functions in T cells via association with CD28 (2011)
  • Author(s): Kong, K-F., Yokosuka, T., Canonigo-Balancio, A.J., et al
  • Journal Title: Nat.Immunol. Volume: 12 Issue: 11 Pages: 1105-1112
  • DOI: 10.1038/ni.2120
  • Peer Reviewed
• [Presentation] Balance of T cell activation and suppression controlled by Cbl-b-mediated ubiquitination of TCR microclusters (2016)
  • Author(s): Tadashi Yokosuka
  • Organizer: MEXT Research Project Symposium
  • Place of Presentation: 理化学研究所（横浜）
  • Year and Date: 2016-03-02
  • Int'l Joint Research / Invited
• [Presentation] Cytoskeletal regulation of the clustering of a Ras-GEF, RasGRP1, upon T cell activation (2015)
  • Author(s): Tadashi Yokosuka, Akiko Hashimoto-Tane, Masae Furuhata, Hiroko Toyoda, Takashi Saito
  • Organizer: 第44回日本免疫学会総会学術集会
  • Place of Presentation: 札幌コンベンションセンター（札幌）
  • Year and Date: 2015-11-18
• [Presentation] 分子イメージングが拓くT細胞活性化の時空間的制御機構 (2015)
  • Author(s): 横須賀忠
  • Organizer: 第14回四国免疫フォーラム
  • Place of Presentation: 愛媛大学（松山）
  • Year and Date: 2015-06-20
  • Invited
• [Presentation] Cytoskeletal regulation of the clustering of a Ras-GEF, RasGRP1, upon T cell activation (2015)
  • Author(s): Tadashi Yokosuka, Akiko Hashimoto-Tane, Takashi Saito
  • Organizer: 第25回京都T細胞カンファランス
  • Place of Presentation: 京都大学（京都）
  • Year and Date: 2015-05-15
• [Presentation] Subcellular imaging of the E3 ubiquitin ligases, c-Cbl and Cbl-b, to control T cell activation signals through ubiquitin clustering at TCR microclusters (2014)
  • Author(s): Tadashi Yokosuka, Akiko Hashimoto-Tane, Takashi Saito
  • Organizer: 第42回日本免疫学会総会学術集会
  • Place of Presentation: 京都国際会議場（京都）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] “Microsynapse” structure supporting TCR microclusters augments T cell activation (2014)
  • Author(s): Akiko Hashimoto-Tane, Tadashi Yokosuka, Takashi Saito
  • Organizer: 第42回日本免疫学会総会学術集会
  • Place of Presentation: 京都国際会議場（京都）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Molecular imaging unveils the dynamic regulation of T cell activation (2014)
  • Author(s): Tadashi Yokosuka, Akiko Hashimoto-Tane, Takashi Saito
  • Organizer: 第18回日本がん免疫学会総会
  • Place of Presentation: ひめ銀ホール（松山）
  • Year and Date: 2014-07-30 – 2014-08-01
  • Invited
• [Presentation] Distinct signalosome formation by two Ras-GEFs to activate the Ras-MAPK pathway in T cell signaling (2014)
  • Author(s): Tadashi Yokosuka, Akiko Hashimoto-Tane, Takashi Saito
  • Organizer: 第24回京都T細胞カンファランス
  • Place of Presentation: 京都大学（京都）
  • Year and Date: 2014-05-16 – 2014-05-17
• [Presentation] Basilic, a lymphoid-specific protein essential for CD28 costimulation and regulatory T cell development (2013)
  • Author(s): Marie Malissen, Yinming Liangv, Margot Cucchetti, Romain Roncagalli, Tadashi Yokosuka, Takashi Saito, Christoph Wulfing, Bernard Malissen,
  • Organizer: International Congress of Immunology 2013
  • Place of Presentation: Italia Milano
• [Presentation] Distinct signalosome formation by two Ras-GEFs to activate the Ras-MAPK pathway in T cell signaling (2013)
  • Author(s): Tadashi Yokosuka, Akiko Hashimoto-Tane, Takashi Saito
  • Organizer: 第42回日本免疫学会総会学術集会
  • Place of Presentation: 幕張メッセ（千葉）
• [Presentation] Arp2/3 complex-mediated actin-nucleation supports T cell receptor microcluster (2013)
  • Author(s): Akiko Hashimoto-Tane, Tadashi Yokosuka, Takashi Saito
  • Organizer: 第42回日本免疫学会総会学術集会
  • Place of Presentation: 千葉
• [Presentation] Dynamic and cytoskeletal regulation of T cell activation (2013)
  • Author(s): Takashi Saito, Tadashi Yokosuka, Akiko Hashimoto-Tane
  • Organizer: RIKEN RCAI-University of Michigan Joint Workshop
  • Place of Presentation: Detroit, USA
  • Invited
• [Presentation] Negative costimulatory microclusters inhibiting T cell-mediated inflammation (2013)
  • Author(s): Tadashi Yokosuka, Akiko Hashimoto-Tane, Takashi Saito
  • Organizer: JST-CREST International Symposium
  • Place of Presentation: 学術総合センター（東京）
• [Presentation] Essential role for intra- and intermolecular SH3-GUK interactions of CARMA1 in antigen receptor-induced NF-κB and JNK activation (2012)
  • Author(s): Hiromitsu Hara, Tadashi Yokosuka, Hideki Hirakawa, Chitose Ishihara, Shinsuke Yasukawa, Haruhiko Koseki, Hiroki Yoshida, Takashi Saito
  • Organizer: 第41回日本免疫学会総会学術集会
  • Place of Presentation: 神戸国際会議場（神戸）
• [Presentation] Ｔ細胞の抗原認識と免疫応答を司る活性化シグナルユニットの研究
  • Author(s): 横須賀忠
  • Organizer: 第４回千葉医学会賞受賞講演
  • Place of Presentation: 千葉大学医学部（千葉）
  • Invited
• [Remarks] 東京医科大学免疫学分野
  • URL: http://tokyo-med-imm.jimdo.com/
• [Remarks] 東京医科大学免疫学分野
  • URL: http://www.tokyo-med.ac.jp/faculty/med/course/course18.html