Mechanisms of T cell activation regulation by inhibitory microclusters

• Project/Area Number: 21590548
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: YOKOSUKA Tadashi 独立行政法人理化学研究所, 免疫シグナル研究グループ, 上級研究員 (10359599)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• 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 / 抗原認識 / リンパ球 / バイオイメージング / 受容体・細胞内シグナル伝達 / 獲得免疫

Research Abstract

Imaging analysis of the negative costimulatory receptor, CTLA-4, revealed the novel mechanism of T cell activation regulation. CTLA-4 formed clusters at the center of the immunological synapse and interfered the formation of the signaling molecule complex, which is composed by the positive costimulatory receptor CD28, kinases, and scaffold proteins. These results suggest that T cell activation is cooperatively regulated by both T cell receptor. CD28 microclusters and the CTLA-4-mediated inhibitory microclusters.

Research Products

• [Journal Article] Dynein-driven transport of T cell receptor microclusters regulates immune synapse formation and T cell activation (2011)
  • Author(s): Hashimoto-Tane A, Yokosuka T, Sakata-Sogawa K, Sakuma M, Ishihara C, Tokunaga M, Saito T.
  • Journal Title: Immunity Volume: 34(6) Pages: 919-931
  • Peer Reviewed
• [Journal Article] CIN85 regulates the canonical NF-κB pathway and subsequent B cell responses (2011)
  • Author(s): Kometani K, Yamada T, Sasaki Y, Yokosuka T, Saito T, Rajewsky K, Ishiai M, Hikida M, Kurosaki T.
  • Journal Title: J Exp Med Volume: 208(7) Pages: 1447-1457
  • Peer Reviewed
• [Journal Article] A motif in the V3 domain of the kinase PKC-θdetermines 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, Isakov N, Saito T, Altman A.
  • Journal Title: Nat. Immunol Volume: 12(11) Pages: 1105-12
  • 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
• [Journal Article] CIN85 drives B cell responses by linking BCR signals to the canonical NF-κB pathway (2011)
  • Author(s): Kometani, K., Yamada, T., Sasaki, Y., Yokosuka, T., Saito, T., Rajewsky, K., Ishiai, M., Hikida, M. and Kurosaki, T
  • Journal Title: J. Exp. Med Volume: 208 Issue: 7 Pages: 1447-1457
  • DOI: 10.1084/jem.20102665
  • Peer Reviewed
• [Journal Article] Dynein-driven transport of T cell receptor microclusters forms the cSMAC and regulates T cell activation (2011)
  • Author(s): Hashimoto-Tane A, Yokosuka T, Sakata-Sogawa K, Sakuma M, Ishihara C, Tokunaga M, Saito T
  • Journal Title: Immunity Volume: Vol.34 Issue: 6 Pages: 919-931
  • DOI: 10.1016/j.immuni.2011.05.012
  • Peer Reviewed
• [Journal Article] Dynamic regulation of T cell activation and co-stimulation through TCR-microclusters (2010)
  • Author(s): Saito T, Yokosuka T, Hashimoto-Tane A.
  • Journal Title: FEBS Lett Volume: 584 Pages: 4865-4871
• [Journal Article] Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation (2010)
  • Author(s): Yokosuka T, Kobayashi W, Takamatsu M, Sakata-Sogaw, K, Zen H, Hashimoto-Tane A, Yagita H, Tokunaga M, Saito T.
  • Journal Title: Immunity Volume: 33(3) Pages: 326-339
  • Peer Reviewed
• [Journal Article] T cell receptor-microclusters critical for T-cell activation are formed independently of lipid raft clustering (2010)
  • Author(s): Hashimoto-Tane A, Yokosuka T, Ishihara C, Sakuma M, Kobayashi W, Saito T.
  • Journal Title: Mol Cel Biol Volume: 30(14) Pages: 3421-3429
  • Peer Reviewed
• [Journal Article] T cell receptor-microclusters critical for T-cell activation are formed independently of lipid raft clustering (2010)
  • Author(s): Akiko Hashimoto-Tane
  • Journal Title: Molecular and Cellular Biology Volume: 30 Pages: 3421-3429
  • Peer Reviewed
• [Journal Article] Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation (2010)
  • Author(s): Tadashi Yokosuka
  • Journal Title: Immunity Volume: 33 Pages: 326-339
  • Peer Reviewed
• [Journal Article] Dynamic regulation of T cell activation and co-stimulation through TCR-microclusters (2010)
  • Author(s): Takashi Saito
  • Journal Title: FEBS Letters Volume: 584 Pages: 4865-4871
  • Peer Reviewed
• [Journal Article] (2010)
  • Author(s): Tadashi Yokosuka
  • Journal Title: Immunological Synapse(Current Topics in Microbiology and Immunology)(Springer-Verlag Berlin Heidelberg) Pages: 81-107
• [Journal Article] CRTAM confers late-stage activation of CD8+T cells to regulate retention within lymph node (2009)
  • Author(s): Takeuchi A, Itoh Y, Takumi A, Ishihara C, Arase N, Yokosuka T, Koseki H, Yamasaki S, Takai Y, Miyoshi J, Ogasawara K, Saito T.
  • Journal Title: J Immunol Volume: 183(7) Pages: 4220-4228
  • Peer Reviewed
• [Journal Article] Dynamic regulation of T-cell costimulation through TCR-CD28 microclusters (2009)
  • Author(s): Yokosuka T, Saito T.
  • Journal Title: Immunol Rev Volume: 229(1) Pages: 27-40
• [Journal Article] Dynamic regulation of T-cell costimulation through TCR-CD28 microclusters (2009)
  • Author(s): Tadashi Yokosuka
  • Journal Title: Immnological Review 299 Pages: 27-40
  • Peer Reviewed
• [Journal Article] CRTAM confers late-stage activation of CD8+ T cells to regulate retention within lymph node (2009)
  • Author(s): Arata Takeuchi
  • Journal Title: Journal of Immunology 183 Pages: 4220-4228
  • Peer Reviewed
• [Presentation] Negative regulation of TCR signaling by PD-1 microclusters (2012)
  • Author(s): Yokosuka T, Saito T
  • Organizer: The 4th Joint RCAI-LIAI Workshop
  • Place of Presentation: La Jolla, CA. USA
  • Year and Date: 2012-07-08
• [Presentation] Negative regulation of TCR signaling by PD-1 microclusters (2012)
  • Author(s): Takashi Saito
  • Organizer: Keystone Symposia-Regulation of Lymphocyte Signaling
  • Place of Presentation: Keystone, USA
  • Year and Date: 2012-03-15
• [Presentation] 免疫シナプス形成を担うダイニンによるT細胞抗原受容体運搬の分子機構 (2012)
  • Author(s): 多根(橋本)彰子、横須賀忠、斉藤隆
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 京都
  • Year and Date: 2012-03-08
• [Presentation] Negative regulation of TCR signaling by PD-1 microcluster (2012)
  • Author(s): Yokosuka T, Saito T
  • Organizer: Keystone Symposia-Regulation of Lymphocyte Signaling
  • Place of Presentation: Keystone, CO. USA
• [Presentation] SH3-Guk domain regulating Carma1 micro-cluster formation is essential for antigen receptor-induced NF-κB activation (2011)
  • Author(s): Hiromitsu Hara
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-15
• [Presentation] Dynamic regulation of T cell activation by TCR microclusters (2011)
  • Author(s): Tadashi Yokosuka
  • Organizer: 2nd CSI/JSI/KAI Joint symposium on Immunology
  • Place of Presentation: 大阪(招待講演)
  • Year and Date: 2011-12-06
• [Presentation] Imaging of T cell activation regulation : -Negative regulation of TCR signaling by PD-1 microcluster- (2011)
  • Author(s): Takashi Saito
  • Organizer: University of Michigan-RCAI Joint Workshop
  • Place of Presentation: 横浜(招待講演)
  • Year and Date: 2011-12-01
• [Presentation] Negative regulation of TCR signaling by PD-1 microclusters (2011)
  • Author(s): Takashi Saito
  • Organizer: The 4th Joint RCAI-LIAI Workshop
  • Place of Presentation: La Jolla, USA(招待講演)
  • Year and Date: 2011-12-01
• [Presentation] The PD-1 microclusters : negative costimulatory signalosome directly targeting TCR downstream (2011)
  • Author(s): Tadashi Yokosuka
  • Organizer: 第40回日本免疫学会総会学術集会
  • Place of Presentation: 千葉(招待講演)
  • Year and Date: 2011-11-28
• [Presentation] Spatiotemporal regulation of T cell activation and costimulation (2011)
  • Author(s): Takashi Saito
  • Organizer: 1st POSTECH International Symposium of Bio-Imaging
  • Place of Presentation: Pohang, Korea(招待講演)
  • Year and Date: 2011-09-30
• [Presentation] 分子イメージングが拓くT細胞活性化の制御機構 (2011)
  • Author(s): 横須賀忠
  • Organizer: 第20回日本バイオイメージング学会学術集会
  • Place of Presentation: 千歳(招待講演)
  • Year and Date: 2011-09-02
• [Presentation] Spatiotemporal regulation of T cell co-stimulation (2011)
  • Author(s): Takashi Saito
  • Organizer: FASEB Summer Conferences 2011
  • Place of Presentation: Snowmass Village, USA(招待講演)
  • Year and Date: 2011-06-23
• [Presentation] PD-1マイクロクラスターによるT細胞活性化制御機構の解明 (2011)
  • Author(s): 横須賀忠
  • Organizer: 第21回Kyoto T Cell Conference
  • Place of Presentation: 京都
  • Year and Date: 2011-06-10
• [Presentation] Visualizing the dynamics of immune systems by TIRF (2011)
  • Author(s): Takashi Saito
  • Organizer: XXVI Congress of the International Society for Advancement of Cytometry
  • Place of Presentation: Baltimore, USA(招待講演)
  • Year and Date: 2011-05-24
• [Presentation] Dynein-driven transport of TCR microclusters forms Immune synapse and regulates T cell activation. (2011)
  • Author(s): Akiko Hashimoto-Tane
  • Organizer: 第84回日本薬理学会年会(The 84th Annual Meeting of The Japanese Pharmacology Society)
  • Place of Presentation: 横浜
  • Year and Date: 2011-03-23
• [Presentation] Dynamic Regulation of T-cell Activation by TCR Microclusters (2011)
  • Author(s): Yokosuka T
  • Organizer: 東京理科大学生命科学研究所セミナー
  • Place of Presentation: 野田
  • Year and Date: 2011-01-11
• [Presentation] SH3-Guk domain regulating Carma1 micro-cluster formation is essential for antigen receptor-induced NF-κB activation (2011)
  • Author(s): Hara H, Yokosuka T, Ishihara C, Yasukawa S, Hirakawa H, Iizasa E, Yoshida H, Saito T.
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: Yokohama
• [Presentation] Dynamic regulation of T cell activation by TCR microclusters (2011)
  • Author(s): Yokosuka T
  • Organizer: 2nd CSI/JSI/KAI Joint Symposium on Immunology "Regulation of Immune Responses in Health and Diseases"
  • Place of Presentation: Osaka
• [Presentation] Imaging of T cell activation regulation :-Negative regulation of TCR signaling by PD-1 microcluster- (2011)
  • Author(s): Yokosuka T, Saito T
  • Organizer: University of Michigan-RCAI Joint Workshop
  • Place of Presentation: Yokohama
• [Presentation] 免疫シナプスにおけるダイニンによるT細胞受容体ミクロクラスター運搬の分子機構 (2011)
  • Author(s): 多根(橋本)彰子、横須賀忠、斉藤隆
  • Organizer: 第40回日本免疫学会総会学術集会
  • Place of Presentation: 千葉
• [Presentation] The PD-1 microclusters : negative costimulatory signalosomes directly targeting TCR downstream (2011)
  • Author(s): Yokosuka T, Saito T
  • Organizer: 第40回日本免疫学会総会学術集会
  • Place of Presentation: 千葉
• [Presentation] Spatiotemporal regulation of T cell activation and costimulation (2011)
  • Author(s): Saito T, Yokosuka T, Hashimoto-Tane A.
  • Organizer: 1st POSTECH International Symposium of Bio-Imaging
  • Place of Presentation: Pohang, Korea
• [Presentation] 分子イメージングが拓くT細胞活性化の制御機構 (2011)
  • Author(s): 横須賀忠
  • Organizer: 第20回日本バイオイメージング学会学術集会
  • Place of Presentation: 千歳
• [Presentation] Spatiotemporal regulation of T cell co-stimulation (2011)
  • Author(s): Saito T, Yokosuka T, Tane-Hashimoto A.
  • Organizer: FASEB Summer Conferences Signal Transduction in the Immune System
  • Place of Presentation: Snowmass Village, CO
• [Presentation] PD-1マイクロクラスターによるT細胞活性化制御機構の解明 (2011)
  • Author(s): 横須賀忠
  • Organizer: Kyoto T Cell Conference
  • Place of Presentation: Kyoto
• [Presentation] Visualising the dynamics of immune synapse by TIRF (2011)
  • Author(s): Saito T, Yokosuka T, Tane-Hashimoto A, Sakata-Sogawa K, Tokunaga M.
  • Organizer: XXVI Congress of the International Society for Advancement of Cytometry(CYTO2011)
  • Place of Presentation: Baltimore, MD, USA
• [Presentation] Dynein-driven transport of TCR microclusters forms Immune synapse and regulates T cell activation (2011)
  • Author(s): Hashimoto-Tane A, Yokosuka T, Sakuma M, Saito T.
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: 横浜
• [Presentation] Dynamic regulation of T-cell activation by TCR microclusters (2011)
  • Author(s): Yokosuka T
  • Organizer: RIKEN 2011 Joint Retreat
  • Place of Presentation: Kakegawa
• [Presentation] Dynamic Regulation of T-cell Activation by TCR Microclusters (2010)
  • Author(s): Tadashi Yokosuka
  • Organizer: 第16回武田科学振興財団生命科学シンポジウム(The 16th Takeda Science Foundation Symposium on Bioscience)
  • Place of Presentation: 東京
  • Year and Date: 2010-12-01
• [Presentation] 分子イメージングが拓くT細胞活性化の制御機構 (2010)
  • Author(s): 横須賀忠
  • Organizer: 第2回バイオフロンティアセミナー「免疫・疾患制御に向けたイメージング解析」
  • Place of Presentation: 東京
  • Year and Date: 2010-11-18
• [Presentation] CRTAM confers late-stage activation of CD8+T cells to regulate retention within lymph node (2010)
  • Author(s): Arata Takeuchi
  • Organizer: 14th International Congress of Immunology(第14回国際免疫学会議)
  • Place of Presentation: 神戸
  • Year and Date: 2010-08-26
• [Presentation] Dynamic regulation of T-cell costimulation by TCR microclusters and the c-SNAG (2010)
  • Author(s): Tadashi Yokosuka
  • Organizer: 14th International Congress of Immunology(第14回国際免疫学会議)
  • Place of Presentation: 神戸
  • Year and Date: 2010-08-23
• [Presentation] Dynein-mediated translocation of TCR microclusters along microtubules to form cSMAC during T cell activation (2010)
  • Author(s): Akiko Hashimoto-Tane
  • Organizer: 14th International Congress of Immunology(第14回国際免疫学会議)
  • Place of Presentation: 神戸
  • Year and Date: 2010-08-23
• [Presentation] Dynamic regulation of T-cell costimulation by TCR microclusters and the c-SMAC (2010)
  • Author(s): Tadashi Yokosuka
  • Organizer: 第13回国際細胞膜研究フォーラム/第6回iCeMS国際シンポジウム
  • Place of Presentation: 京都市、ホテルフジタ京都
  • Year and Date: 2010-01-27
• [Presentation] Dynamic Regulation of T-cell Activation by TCR Microclusters (2010)
  • Author(s): Yokosuka T, Saito T
  • Organizer: 第16回武田科学振興財団生命科学シンポジウム
  • Place of Presentation: 東京
• [Presentation] Dynein-mediated translocation of TCR microclusters along microtubules to form c-SMAC during T cell activation (2010)
  • Author(s): Hashimoto-Tane A, Yokosuka T, Sakuma M, Saito T.
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: 神戸
• [Presentation] CRTAM confers late-stage activation of CD8+T cells to regulate retention within lymph node (2010)
  • Author(s): Takeuchi A, Itoh A, Yokosuka T, Ogasawara K, Saito T
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: 神戸
• [Presentation] Dynamic regulation of T-cell costimulation by TCR microclusters and the c-SMAC (2010)
  • Author(s): Yokosuka T, Sakata-Sogawa K, Tokunaga M, Saito T
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: 神戸
• [Presentation] T細胞の免疫シナプス形成と胸腺選択性との機能的相関の解析 (2010)
  • Author(s): 横須賀忠、斉藤隆
  • Organizer: 第20回Kyoto T Cell Conference(KTCC)学術集会
  • Place of Presentation: 京都
• [Presentation] Dynein-mediated translocation of TCR microclusters along microtubules to form cSMAC (2010)
  • Author(s): Hashimoto-Tane A, Yokosuka T, Saito T.
  • Organizer: Keystone Symposia(Breckenridge
  • Place of Presentation: CO. USA
• [Presentation] Dynamic regulation of T-cell costimulation by TCR microclusters and the c-SMAC (2010)
  • Author(s): Yokosuka T
  • Organizer: The 13th International Membrane Research Forum/The 6th iCeMS International Symposium, Featuring Membrane Meso Mechanisms
  • Place of Presentation: Kyoto
• [Presentation] Dynamic regulation of T-cell costimulation by TCR microclusters and the c-SMAC (2009)
  • Author(s): Tadashi Yokosuka
  • Organizer: 第39回日本免疫学会総会・学術集会
  • Place of Presentation: 大阪市 国際会議場
  • Year and Date: 2009-12-03
• [Presentation] T細胞活性化及びcSMAC形成につながる微小管モーター・ダイニンによるTCRミクロクラスターの移動/Dynein-mediated translocation of TCR micro-clusters along microtubules to form cSMAC during T cell activation (2009)
  • Author(s): 橋本彰子(多根)
  • Organizer: 第39回日本免疫学会総会・学術集会
  • Place of Presentation: 大阪市 国際会議場
  • Year and Date: 2009-12-03
• [Presentation] Dynamic regulation of T-cell costimulation by TCR microclusters (2009)
  • Author(s): Tadashi Yokosuka
  • Organizer: FASEB Summer Research Conferences
  • Place of Presentation: Snowmass Village(USA)
  • Year and Date: 2009-06-24
• [Presentation] Dynamic assembly of signaling complex for positive and negative costimulation of T cell activation (2009)
  • Author(s): Takashi Saito
  • Organizer: The 5th International Workshop of Kyoto T Cell Conference 2009
  • Place of Presentation: 京都市、京大芝蘭会館
  • Year and Date: 2009-06-02
• [Presentation] TCR microclusters move along microtubules in early T cell activation (2009)
  • Author(s): Akiko Hashimoto-Tane
  • Organizer: The 5th International Workshop of Kyoto T Cell Conference 2009
  • Place of Presentation: 京都市、京大芝蘭会館
  • Year and Date: 2009-06-02
• [Presentation] T細胞活性化及びcSMAC形成につながる微小管モーター・ダイニンによるTCRミクロクラスターの移動 (2009)
  • Author(s): 橋本彰子(多根)、横須賀忠、斉藤隆
  • Organizer: 第39回日本免疫学会総会・学術集会
  • Place of Presentation: 大阪
• [Presentation] Imaging of Immune Responses Dynamic regulation of T-cell costimulation by TCR microclusters and the c-SMAC (2009)
  • Author(s): Yokosuka T, Saito T
  • Organizer: 第39回日本免疫学会総会・学術集会
  • Place of Presentation: 大阪
• [Presentation] Dynamic regulation of T-cell costimulation by TCR microclusters (2009)
  • Author(s): Yokosuka T, Saito T
  • Organizer: FASEB Summer Research Conferences
  • Place of Presentation: Snowmass Village, CO
• [Presentation] TCR microclusters move along microtubules in early T cell activation (2009)
  • Author(s): Hashimoto-Tane A, Yokosuka T, Ishihara C, Saito T.
  • Organizer: The 5th International Workshop of Kyoto T Cell Conference
  • Place of Presentation: Kyoto
• [Presentation] Dynamic assembly of signaling complex for positive and negative costimulation of T cell activation (2009)
  • Author(s): Yokosuka T and Saito T
  • Organizer: The 5th International Workshop of Kyoto T Cell
  • Place of Presentation: Kyoto
• [Book] CTLA-4によるT細胞活性化制御の分子機序,臨床免疫・アレルギー科 (2012)
  • Author(s): 横須賀忠
• [Book] 免疫の辞典 (2011)
  • Author(s): 横須賀忠
  • Publisher: 朝倉書店
• [Book] T細胞の活性化に対する補助刺激受容体CTLA-4による時空間的な制御機構の解明 (2010)
  • Author(s): 横須賀忠、斉藤隆
  • Publisher: ライフサイエンス新着論文レビュー
• [Book] The immunological synapse, TCR microclusters, and T cell activation (2010)
  • Author(s): Yokosuka T, Saito T.
  • Publisher: Springer-Verlag Berlin Heidelberg
• [Remarks]
  • URL: http://web.rcai.riken.jp/en/labo/signaling/