制御性T細胞機能の分子的基礎に関する研究

2009 Fiscal Year Annual Research Report

• Project/Area Number: 20002007
• Research Institution: Kyoto University
• Principal Investigator: 坂口 志文 Kyoto University, 再生医科学研究所, 教授 (30280770)
• Co-Investigator(Kenkyū-buntansha): 山口 智之 京都大学, 再生医科学研究所, 助教 (80402791)
• Keywords: FOXP3 / 制御性T細胞 / 自己免疫病 / Tリンパ球 / CTLA-4

Research Abstract

制御性T細胞(Regulatory T cell、以下Tregと略)による抑制機構および胸腺におけるTregのT細胞抗原レセプター(TCR)認識範囲(TCRレパトア)の形成機構を解析した。Treg特異的CTLA-4分子の欠損により制御性T細胞は抑制能を失う。逆に、CD4T細胞特異的にCTLA-4を発現するトランスジェニック(Tg)マウスで、正常T細胞がCTLA-4を高発現するならば、制御性T細胞と同じく抑制能を発揮するか検討した。また、制御性T細胞の特徴として高親和性インターリューキン-2(IL-2)レセプターを高発現することから、IL-2が制御性T細胞の抑制能に関与するか検討した。その結果、IL-2遺伝子欠損(KO)マウスとCTLA-4Tgマウスを掛け合わせて作製したIL-2を産生せずCTLA-4を構成的に高発現するCD4T細胞は、抗原刺激によって活性化されると、試験管内でも生体内でも強力な抑制能を示した。この抑制能は、活性化IL-2KO/CTLA-4TgT細胞が、周囲からIL-2を吸収し、またTg CTLA-4がCD80/CD86共刺激分子と強結合し、その結果レスポンダーT細胞に対するCD28シグナルを阻害することによる。さらに、CTLA-4Tgマウスを用いて、CTLA-4の高発現が、制御性T細胞の胸腺での発生、分化に及ぼす効果を検討したところ、CTLA-4TgT細胞のTCRレパトアは、有意に自己反応性に偏っていた。逆に、CTLA-4欠損制御性T細胞のTCRレパトアは自己反応性を失っていた。これらの結果は、胸腺でのT細胞選択において、末梢と同じくCTLA-4の高発現によりCD28シグナルが減弱すると、それを補償できる強いTCR刺激を生じるT細胞のみが選択される。即ち、制御性T細胞におけるCTLA-4の高発現は、末梢での抑制機構のみならず胸腺での発生に重要である。

Research Products

• [Journal Article] Chronic arthritis leads to disturbances in the bone collagen network. (2010)
  • Author(s): Caetano-Lopes J, Nery AM, Canhao H, Duarte J, Cascao R, Rodrigues A, Perpetuo IP, Abdulghani S, Amaral PM, Sakaguchi S, Konttinen YT, Graca L, Vaz MF, Fonseca JE.
  • Journal Title: Arthritis Res Ther. 12(1):R9
  • Peer Reviewed
• [Journal Article] Regulation of Zap 70 expression during thymic development allows temporal separation of CD4 and CD8 repertoire selection at different signaling thresholds. (2010)
  • Author(s): Saini M, Sinclair C, Marshall D, Tolaini M, Sakaguchi S, Seddon B.
  • Journal Title: Science Signaling. 3(114):ra23.
  • Peer Reviewed
• [Journal Article] Multiple antitumor mechanisms downstream of prophylactic regulatory T-cell depletion. (2010)
  • Author(s): Teng, M.W., Swann, J.B., von Scheidt B, Sharkey, J., Zerafa, N., McLaughlin, N., Yamaguchi, T., Sakaguchi, S., Darcy, P.K., Smyth, M.J.
  • Journal Title: Cancer Res. 70 Pages: 2665-2674
  • Peer Reviewed
• [Journal Article] Therapeutic Glucocorticoid-Induced TNF Receptor-Mediated Amplification of CD4+ T Cell Responses Enhances Antiparasitic Immunity. (2010)
  • Author(s): Haque A, Stanley AC, Amante FH, Rivera FD, Zhou Y, Kuns RD, Yardley V, Sakaguchi S, Hill GR, Engwerda CR.
  • Journal Title: J Immunol. 184 Pages: 2583-2592
  • Peer Reviewed
• [Journal Article] Functional delineation and differentiation dynamics of human CD4(+) Tcells expressing the FoxP3 transcription factor. (2009)
  • Author(s): Miyara, M., Shima, T., Kitoh, A., Yoshioka, Y., Niwa, A., Taflin, C., Heike, T., Valeyre, D., Mathian, A., Nakahata, T., Yamaguchi T., Nomura, T., Wing, K., Ono, M., Amoura, Z., Guy Gorochov, G., Sakaguchi, S.
  • Journal Title: Immunity. 30 Pages: 899-911
  • Peer Reviewed
• [Journal Article] Indispensable role of Runxl/Cbf complexes for in vivo suppressive function of FoxP^<3+> regulatory T cells. (2009)
  • Author(s): Kitoh, A., Ono, M., Naoe, Y., Ohkura, N., Yamaguchi, T, Yaguchi H., Kitabayashi, I., Tsukada, T., Nomura, T., Miyachi,Y., Taniuchi, I., Sakaguchi, S.
  • Journal Title: Immunity. 31 Pages: 609-620
  • Peer Reviewed
• [Journal Article] Differential control of alloantigen-specific regulatory T cells and effector T cells by anti-CD4 and other agents in establishing transplantation tolerance. (2009)
  • Author(s): Nagahama, K., Fehervari, Z., Oida, T., Ogawa, 0., Sakaguchi, S.
  • Journal Title: Int.Immunol. 21 Pages: 379-391
  • Peer Reviewed
• [Journal Article] A novel modifier of regulatory T cells (2009)
  • Author(s): Ohkura, N,. Sakaguchi, S.
  • Journal Title: Nat Immunol. 10 Pages: 385-686
  • Peer Reviewed
• [Journal Article] Therapeutic approaches to allergy and autoimmunity based on FoxP3+ regulatory T-cell activation and expansion. (2009)
  • Author(s): Miyara, M., Wing, K., Sakaguchi, S.
  • Journal Title: J Allergy Clin Immunol. 123 Pages: 749-755
  • Peer Reviewed
• [Journal Article] Dynamics of peripheral tolerance and immune regulation mediated by Treg. (2009)
  • Author(s): Sakaguchi, S., Wing, K., Yamaguchi, T.
  • Journal Title: Eur. J.Immunol. 39 Pages: 2331-2336
  • Peer Reviewed
• [Journal Article] Regulatory T cells : how do they suppress immune responses? (2009)
  • Author(s): Sakaguchi S, Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T.
  • Journal Title: Int. Immunol. 21 Pages: 1105-1111
  • Peer Reviewed
• [Journal Article] Regulatory T cells exert checks and balances on self-tolerance and autoimmunity. (2009)
  • Author(s): Wing K, Sakaguchi S.
  • Journal Title: Nat. Immunol. 11 Pages: 7-13
  • Peer Reviewed
• [Journal Article] Gamma/delta T cells are the predominant source of interleukin-17 in affected joints in collagen-induced arthritis, but not in rheumatoid arthritis (2009)
  • Author(s): Ito Y, Usui T, Kobayashi S, Iguchi-Hashimoto M, Ito H, Yoshitomi H, Nakamura T, Shimizu M, Kawabata D, Yukawa N, Hashimoto M, Sakaguchi N, Sakaguchis Yoshifuji H, Nojima T, Ohmura K, Fujii T, Mimori T.
  • Journal Title: Arthritis Rheum. 60 Pages: 2294-2303
  • Peer Reviewed
• [Journal Article] CD4+CD25-LAG3+ regulatory T cells controlled by the transcription factor Egr-2. (2009)
  • Author(s): Okamura T, Fujio K, Shibuya M, Sumitomo S, Shoda H, Sakaguchi S, Yamamoto K.
  • Journal Title: Proc Natl Acad Sci U S A. 106 Pages: 13974-13949
  • Peer Reviewed
• [Journal Article] Constitutive expression of IDO by dendritic cells of mesenteric lymph nodes : functional involvement of the CTLA-4B7 and CCL22/CCR4 interacoons. (2009)
  • Author(s): Onodera T, Jang MH, Guo Z, Yamasaki M, Hirata T, Bai Z, Tsuji NM, Nagakubo D, Yoshie O, Sakaguchi S, Takikawa O, Miyasaka M.
  • Journal Title: J.Immunol. 183 Pages: 5608-5614
  • Peer Reviewed
• [Journal Article] Requirement of protocol biopsy before and after complete cessation of immunosuppression following liver transplantation. (2009)
  • Author(s): Yoshitomi, M., Koshiba, T., Haga, H., Li, Y., Zhao, X., Cheng, D., Miyagawa, A., Sakashita, H., Tsuruyama T., Ueda, M., Wood, K., Sakaguchi S., Manabe, T., Tanaka, K., Uemoto, S.
  • Journal Title: Transplantation. 87 Pages: 606-614
  • Peer Reviewed
• [Journal Article] Immune rejection of mouse tumors expressing mutated self. (2009)
  • Author(s): Duan F, Lin Y, Liu C, Engelhorn ME, Cohen AD, Curran M, Sakaguchi S, Merghoub T, Terzulli S, Wolchok JD, Houghton AN.
  • Journal Title: Cancer Res. 69 Pages: 3545-3553
  • Peer Reviewed
• [Journal Article] Enhancement of T-cell-mediated anti-tumour immunity via the ectopically expressed glucocorticoid-induced tumour necrosis factor receptor-related receptor ligand (GITRL) on tumours. (2009)
  • Author(s): Piao J,Kamimura Y, Iwai H, Cao Y, Kikuchi K, Hashiguchi M, Masunaga T, Jiang H, Tamura K, Sakaguchi S, Azuma M.
  • Journal Title: Immunity. 127 Pages: 489-499
  • Peer Reviewed
• [Journal Article] Therapeutic Immunity by Adoptive Tumor-primed CD4(+)T-cell Transfer in Combination With In Vivo GITR Ligation. (2009)
  • Author(s): Liu, Z., Tian, S., Falo, L.D.Jr, Sakaguchi, S., You, Z.
  • Journal Title: Mol Ther. 17 Pages: 1274-1284
  • Peer Reviewed
• [Presentation] Control of immune responses by regulatory T cells (2010)
  • Author(s): Shimon Sakaguchi
  • Organizer: 8^<th> EAACI-GAZLEN-Immunology Winter School
  • Place of Presentation: Germany,Gralnau, Garmlsah-Partenklrohan
  • Year and Date: 20100211-20100214
• [Presentation] T cell signaling for dominant and recessive self-tolerance (2009)
  • Author(s): Shimon Sakaguchi
  • Organizer: ASI(Australasian Society for Immunology)39^<th> Annual Scientific Meeting
  • Place of Presentation: Australia, Canrad Jupiters Queensland
  • Year and Date: 20091206-20091210
• [Presentation] Tolerance (2009)
  • Author(s): Shimon Sakaguchi
  • Organizer: 10^<th> FIMSA(Federation of Immunological Society of Asia-Oceania)Advanced Immunology Training Course
  • Place of Presentation: Australia, Tanga looma
  • Year and Date: 20091203-20091206
• [Presentation] Regulatory T cells for immune tolerance and tumor immunity (2009)
  • Author(s): Shimon Sakaguchi
  • Organizer: International Symposium on Immunotherapy and immunodeficiency
  • Place of Presentation: Heidelberg, Germany
  • Year and Date: 20091119-20091120
• [Presentation] T cell signaling, regulatory T cells and self-tolerance. (2009)
  • Author(s): Shimon Sakaguchi
  • Organizer: 1^<st> International Conference on Immune Tolerance
  • Place of Presentation: Boston U.S.A.
  • Year and Date: 20091025-20091027
• [Presentation] CTLA-4 Dependent Mechanism of Treg-Mediated In Vivo and In Vitro Suppression in Tumor Immunity (2009)
  • Author(s): Shimon Sakaguchi
  • Organizer: Control of Cancer Immunosuppression The Challenge for Cancer Vaccine Development The XVII^<th> Meeting in the Cancer Research Institute International Cancer Immunotherapy Symposium Series
  • Place of Presentation: New York USA
  • Year and Date: 20090930-20091002
• [Presentation] CTLA-4 for Treg-mediated suppression, Tolerance and Immunoregulation (2009)
  • Author(s): Shimon Sakaguchi
  • Organizer: From basic mechanisms to therapeutic applications, Satellite Symposium of the European Congress of Immunology
  • Place of Presentation: Berlin, Germany
  • Year and Date: 20090911-20090912
• [Presentation] Regulatory T cells for immune tolerance and homeostasis towards their clinical use (2009)
  • Author(s): Shimon Sakaguchi
  • Organizer: TWINCORE-Symposium Infection Research and Beyond
  • Place of Presentation: Hannover Germany
  • Year and Date: 20090909-20090910
• [Presentation] T cell signaling, regulatory T cells and autoimmunity. (2009)
  • Author(s): Shimon Sakaguchi
  • Organizer: Cellular and Genetic View on Autoimmunity. RCAI-JSI International Symposium on Immunology 2009
  • Place of Presentation: 横浜
  • Year and Date: 20090709-20090710
• [Presentation] Control of immune response by regulatory T cells (2009)
  • Author(s): Shimon Sakaguchi
  • Organizer: 45^<th> Joint Committee Meeting Japan-U.S. Cooperative Medical Science Program
  • Place of Presentation: 札幌
  • Year and Date: 20090629-20090630
• [Presentation] Suppression Mechanisms of Foxp3^+ Regulatory T Cells (2009)
  • Author(s): Shimon Sakaguchi
  • Organizer: FOCIS 2009
  • Place of Presentation: San Francisco USA
  • Year and Date: 20090611-20090614
• [Presentation] T cell signaling, regulatory T cells and self-tolerance. (2009)
  • Author(s): Shimon Sakaguchi
  • Organizer: The 5^<th> International Workshop of Kyoto T Cell Conference.
  • Place of Presentation: 京都
  • Year and Date: 20090601-20090604
• [Presentation] Regulatory T cells for immunological tolerance and immune homeostasis (2009)
  • Author(s): Shimon Sakaguchi
  • Organizer: The First International Kishimoto Foundation Symposium Immune Regulation : Present and Future
  • Place of Presentation: 大阪
  • Year and Date: 20090525-20090527
• [Presentation] T cell signaling, regulatory T cells and autoimmunity. (2009)
  • Author(s): Shimon Sakaguchi
  • Organizer: Tolerance and Development. The Foundation des Treilles
  • Place of Presentation: Tourtour France
  • Year and Date: 20090414-20090419