Spatiotemporal regulation of antigen recognition and activation of T cells

2011 Fiscal Year Final Research Report

• Project/Area Number: 19109005
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Immunology
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: SAITO Takashi 独立行政法人理化学研究所, 免疫シグナル研究グループ, グループディレクター (50205655)
• Co-Investigator(Kenkyū-buntansha): 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): 2007 – 2011
• Keywords: 免疫シナプス / ミクロクラスター / シグナル伝達 / 抗原認識 / T細胞 / 細胞活性化 / 副刺激

Research Abstract

T cell activation is induced by TCR-microcluster(MC). We clarified the molecules accumulated within MCs, and the relationship with costimulation signals and lipid raft. Lipid raft does not function as the platform and protein interaction within MCs induce activation. CD28-mediated costimulation recruits PKCθ-Carma1 to cSMAC, whereas the inhibitory costimulation receptor CTLA-4 inhibits by accumulating in cSMAC and kicking off CD28-PKCθfrom the cSMAC. TCR-MCs associate with the dynein complex and translocate along microtubules to form cSMAC.

Research Products

• [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, et al,(6人中5番目)
  • Journal Title: Nat. Immunol Volume: 12 Pages: 1105-12
  • Peer Reviewed
• [Journal Article] Nanocluster formation : More with memory (2011)
  • Author(s): Saito T.
  • Journal Title: Immunity Volume: 35 Pages: 318-320
• [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 Pages: 1447-1457
  • Peer Reviewed
• [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 Pages: 919-931
  • Peer Reviewed
• [Journal Article] Induction of colonic regulatory T cells by indigenous clostridium species (2011)
  • Author(s): Atarashi K, et al,(17人中9番目)
  • Journal Title: Science Volume: 331 Pages: 337-341
  • 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
  • Peer Reviewed
• [Journal Article] Germ-line elimination of electric charge on pre-T-cell receptor(TCR) impairs autonomous signaling for beta-selection and TCR repertoire formation (2010)
  • Author(s): Ishikawa E, et al,(5人中4番目)
  • Journal Title: Proc Natl Acad Sci USA Volume: 107 Pages: 19979-19984
  • Peer Reviewed
• [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-Sogawa K, Zeng H, Hashimoto-Tane A, Yagita H, Tokunaga M, Saito T
  • Journal Title: Immunity Volume: 33 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 and Saito T.
  • Journal Title: Mol. Cel. Biol Volume: 30 Pages: 3421-3429
  • Peer Reviewed
• [Journal Article] Dectin-2 recognition ofτ-mannans and induction of Th17 cell dfferentiation is essential for host defense against Candida albicans (2010)
  • Author(s): Saijo S, et al,(21人中19番目)
  • Journal Title: Immunity Volume: 32 Pages: 681-691
  • Peer Reviewed
• [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, and Saito T.
  • Journal Title: J. Immunol Volume: 183 Pages: 4220-4228
  • Peer Reviewed
• [Journal Article] Dynamic regulation of T-cell costimulation through TCR-CD28 microclusters (2009)
  • Author(s): Yokosuka T and Saito T
  • Journal Title: Immunol. Rev Volume: 229 Pages: 27-40
  • Peer Reviewed
• [Journal Article] CARD9 versus CARMA1 in innate and adaptive immunity (2009)
  • Author(s): Hara H and Saito T.
  • Journal Title: Trends Immunol Volume: 30 Pages: 234-242
  • Peer Reviewed
• [Journal Article] Naturally occurring regulatory dendritic cells regulate murine cutaneous chronic graft-versus-host disease (2009)
  • Author(s): Sato K, et al,(14人中13番目)
  • Journal Title: Blood Volume: 113 Pages: 4780-4789
  • Peer Reviewed
• [Journal Article] C-type lectin Mincle is an activating receptor for pathogenic fungus, Malassezia (2009)
  • Author(s): Yamasaki S, Matsumoto M, Takeuchi O, Matsuzawa T, Ishikawa E, Sakuma M, Tateno H, Uno J, Hirabayashi J, Mikami Y, Takeda K, Akira S, Saito T.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 10 Pages: 1897-1902
  • Peer Reviewed
• [Journal Article] Fc receptorγ-chain, a constitutive component of the IL-3 receptor, is required for IL-3-induced IL-4 production in basophils (2009)
  • Author(s): Hida S, et al,(10人中9番目)
  • Journal Title: Nat Immunol Volume: 10 Pages: 214-222
  • Peer Reviewed
• [Journal Article] Essential role of Rap signal in pre-TCR。Vmediatedυ-selection checkpoint inτυT cell development (2008)
  • Author(s): Kometani K, et al,(9人中7番目)
  • Journal Title: Blood Volume: 112 Pages: 4565-4573
  • Peer Reviewed
• [Journal Article] Spatiotemporal regulation of T cell costimulation by TCR-CD28 microclusters through protein kinase Cθtranslocation (2008)
  • Author(s): Yokosuka T, Kobayashi W, Sakata-Sogawa, K, Takamatsu M, Hashimoto-Tane A, Dustin ML, Tokunaga M, Saito T.
  • Journal Title: Immunity Volume: 29 Pages: 589-601
  • Peer Reviewed
• [Journal Article] Mincle is an ITAM-coupled activating receptor that senses damaged cells (2008)
  • Author(s): Yamasaki S, Ishikawa E, Sakuma M, Hara H, Ogata K, Saito T.
  • Journal Title: Nat. Immunol Volume: 9 Pages: 1179-1188
  • Peer Reviewed
• [Journal Article] Cell type-specific regulation of ITAM-mediated NF-κB activation by the adaptors, CARMA1 and CARD9 (2008)
  • Author(s): Hara H, Ishihara C, Takeuchi A, Xue L, Morris SW, Penninger JM, Yoshida H, Saito T.
  • Journal Title: J. Immunol Volume: 181 Pages: 918-930
  • Peer Reviewed
• [Journal Article] Thymic selection determinesγδT cell effector fate : antigen-naive cells make interleukin-17 and antigen-experienced cells make interferonγ. (2008)
  • Author(s): Jensen KD, et al,(12人中8番目)
  • Journal Title: Immunity Volume: 29 Pages: 90-100
  • Peer Reviewed
• [Journal Article] A lysosomal protein negatively regulate surface T cell antigen receptor expression by promoting CD3ζ-chain degradation (2008)
  • Author(s): Ouchida R, et al,(15人中13番目)
  • Journal Title: Immunity Volume: 29 Pages: 33-43
  • Peer Reviewed
• [Journal Article] Differential contribution of three activating IgG Fc receptors(FcγRI, FcγRIII and FcγRIV) to IgG2a-and IgG2b-induced autoimmune hemolytic anemia in mice (2008)
  • Author(s): Baudino L, et al,(9人中5番目)
  • Journal Title: J. Immunol Volume: 180 Pages: 1948-1953
  • Peer Reviewed
• [Journal Article] Cloning of B cell-specific membrane tetraspanning molecule BTS possessing B cell proliferation-inhibitory function (2007)
  • Author(s): Suenaga T, Arase H, Yamasaki S, Kohno M, Yokosuka T, Takeuchi A, Hattori T, Saito T.
  • Journal Title: Eur. J. Immunol Volume: 37 Pages: 3197-3207
  • Peer Reviewed
• [Journal Article] Diverging signaling events control the pathway of GPVI down-regulation in vivo (2007)
  • Author(s): Rabie T., et al,(8人中6番目)
  • Journal Title: Blood Volume: 110 Pages: 529-535
  • Peer Reviewed
• [Journal Article] TLR2 directly triggers Th1 effector functions (2007)
  • Author(s): Imanishi T, Hara H, Suzuki S, Suzuki N, Akira S, Saito T.
  • Journal Title: J. Immunol Volume: 178 Pages: 6715-6719
  • Peer Reviewed
• [Journal Article] The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors (2007)
  • Author(s): Hara H, et al,(16人中16番目)
  • Journal Title: Nat. Immunol Volume: 8 Pages: 619-629
  • Peer Reviewed
• [Journal Article] LAT and NTAL mediate immunoglobulin E-induced sustained extracellular signal-regulated kinase activation critical for mast cell survival (2007)
  • Author(s): Yamasaki S, Ishikawa E, Sakuma M, Kanagawa O, Cheng AM, Malissen B, Saito T.
  • Journal Title: Mol. Cell. Biol Volume: 27 Pages: 4406-4415
  • Peer Reviewed
• [Journal Article] Molecular basis for pre-TCR-mediated autonomous signaling (2007)
  • Author(s): Yamasaki S, Saito T.
  • Journal Title: Trends. Immunol Volume: 28 Pages: 39-43
  • Peer Reviewed
• [Journal Article] The actin cloud induced by LFA-1.mediated outside-in signals lowers the threshold for T-cell activation (2007)
  • Author(s): Suzuki J-I, Yamasaki S, Wu J, Koretzky GA, Saito T.
  • Journal Title: Blood Volume: 109 Pages: 168-175
  • Peer Reviewed
• [Journal Article] Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2
  • Author(s): Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T.
  • Journal Title: J. Exp. Med Volume: (in press)
  • Peer Reviewed
• [Presentation] Negative regulation of TCR signaling by PD-1 microcluster (2012)
  • Author(s): Yokosuka, T. and Saito, T
  • Organizer: Keystone Symposia-Regulation of Lymphocyte Signaling
  • Place of Presentation: Keystone, CO. USA
  • Year and Date: 2012-03-15
• [Presentation] A. Spatiotemporal regulation of T cell activation and costimulation (2011)
  • Author(s): Saito, T., Yokosuka, T., Hashimoto-Tane
  • Organizer: 1^<st> POSTECH International Symposium of Bio-Imaging
  • Place of Presentation: Pohang, Korea
  • Year and Date: 2011-09-30
• [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
  • Year and Date: 2011-06-23
• [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
  • Year and Date: 2011-05-24
• [Presentation] Immune cell activation under the microscope. World Immune Regulation Meeting-V(WIRM) (2011)
  • Author(s): Saito, T
  • Organizer: Innate and Adaptive Immune Response and Role of Tissue in Immune Regulation
  • Place of Presentation: Davos, Switzerland
  • Year and Date: 2011-03-25
• [Presentation] Spatio-temporal regulation of T cell activation (2010)
  • Author(s): Saito, T
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: 神戸
  • Year and Date: 2010-08-25
• [Presentation] Molecular dynamics for T cell activation and costimulation. Keystone Symposia (2010)
  • Author(s): Saito, T
  • Organizer: Lymphocyte Activation and Gene Expression
  • Place of Presentation: Breckenridge, CO
  • Year and Date: 2010-03-03
• [Presentation] CARD9 and innate immunity (2009)
  • Author(s): Saito, T
  • Organizer: Center for the Study of Inflammatory Bowel Disease 19th Annual Workshop. Integrating Innate an Adaptive Immunity in Complex Human Diseases
  • Place of Presentation: Boston
  • Year and Date: 20091113-14
• [Presentation] Sensing self and non-self danger by ITAM-coupled innate receptor Mincle (2009)
  • Author(s): Saito, T. and Yamasaki, S
  • Organizer: FASEB Summer Research Conferences-Signal Transduction in the Immune System
  • Place of Presentation: Snowmass Village, CO
  • Year and Date: 2009-06-23
• [Presentation] Recognition of damaged self and non-self pathogens by ITAM-coupled C-type lectin, Mincle (2009)
  • Author(s): Yamasaki, S and Saito, T.
  • Organizer: World Immune Regulation Meeting-III
  • Place of Presentation: Davos, Switzerland
  • Year and Date: 2009-03-23
• [Presentation] Dynamic regulation of TCR-and costimulatory signals via microclusters (2008)
  • Author(s): Saito, T
  • Organizer: Cantoblanco Workshops on Biology. Initiation of Antigen Receptor Signaling
  • Place of Presentation: Madrid, Spain
  • Year and Date: 2008-10-22
• [Presentation] Mincle is an ITAM-coupled activating receptor that senses damaged cells (2008)
  • Author(s): Yamasaki, S., Ishikawa, E., Sakuma, M., Hara, H., Ogata, K. and Saito, T.
  • Organizer: The 10th International Symposium on Dendritic Cells
  • Place of Presentation: 神戸
  • Year and Date: 2008-10-03
• [Presentation] Dynamic Regulation of T Cell Co-stimulation by TCR-CD28 Microclusters (2008)
  • Author(s): Yokosuka, T. and Saito, T
  • Organizer: RCAI-JSI International Symposium on Immunology 2008 : Regulation of Immune Homeostasis and Diseases
  • Place of Presentation: Yokohama
  • Year and Date: 2008-06-26
• [Presentation] Differential cellular adaptors mediating innate and adaptive immunity (2008)
  • Author(s): Saito, T
  • Organizer: Hepatic Inflammation and Immunity 2008
  • Place of Presentation: Galveston, TX, USA
  • Year and Date: 2008-01-25
• [Presentation] CRTAM regulates retention of T cells within lymph node and delivery to effecter tissues (2008)
  • Author(s): Saito, T
  • Organizer: Keystone Symposia/Novel Modulators of Leukocyte Traffic
  • Place of Presentation: Keystone, CO. USA
  • Year and Date: 2008-01-16
• [Presentation] Spatiotemporal regulation of lymphocyte activation : Signalsome (2007)
  • Author(s): Yokosuka, T
  • Organizer: TCR-microcluster. National Academy of Engineering 2007 Japan-America Frontiers of Engineering Symposium
  • Place of Presentation: Palo Alto, CA
  • Year and Date: 20071105-07
• [Presentation] Dynamic regulation of T cell activation through TCR micloclusters (2007)
  • Author(s): Saito, T.
  • Organizer: 13^<th> International Congress of Immunology
  • Place of Presentation: Rio de Janeiro, Brazil
  • Year and Date: 2007-08-24
• [Presentation] Initiation and sustenance of T cell activation by TCR microclusters (2007)
  • Author(s): Saito, T.
  • Organizer: 4th International Leukocyte Signal Transduction Workshop : Clinical implications of signaling pathways
  • Place of Presentation: Rhodes, Greece
  • Year and Date: 2007-06-04
• [Presentation] TCR microclusters and co-stimulation for T cell activation (2007)
  • Author(s): Saito, T.
  • Organizer: EMBO Conference Series on "Signaling in the immune system" Lymphocyte antigen receptor and coreceptor signaling
  • Place of Presentation: Siena, Italy
  • Year and Date: 2007-05-26
• [Book] The immunological synapse, TCR microclusters, and T cell activation (2010)
  • Author(s): Yokosuka T and Saito T.
  • Total Pages: 81-107
  • Publisher: Springer-Verlag Berlin Heidelberg
• [Remarks]
  • URL: http://www.rcai.riken.go.jp/group/signaling/index.html
• [Patent(Industrial Property Rights)] 糖鎖認識受容体の新規用途 (2008)
  • Inventor(s): 斉藤隆、山崎晶
  • Industrial Property Rights Holder: 理化学研究所
  • Industrial Property Number: 特許、特願2008-186570
  • Filing Date: 2008-07-17
• [Patent(Industrial Property Rights)] 糖鎖認識受容体の新規用途 (2008)
  • Inventor(s): 斉藤隆、山崎晶
  • Industrial Property Rights Holder: 理化学研究所
  • Industrial Property Number: 特許、特願2008-285948
  • Filing Date: 2008-11-06
• [Patent(Industrial Property Rights)] T細胞分化調節剤(および細胞表面タンパク質間の細胞外領域における相互作用の検出システム) (2007)
  • Inventor(s): 斉藤隆、山崎晶
  • Industrial Property Rights Holder: 理化学研究所
  • Industrial Property Number: 特許、特願2007-539809
  • Filing Date: 2007-03-04