制御性T細胞機能の分子的基礎に関する研究

2011 Fiscal Year Annual Research Report

• Project/Area Number: 20002007
• Research Institution: Osaka University
• Principal Investigator: 坂口 志文 大阪大学, 免疫学フロンティア研究センター, 教授 (30280770)
• Co-Investigator(Kenkyū-buntansha): 山口 智之 大阪大学, 免疫学フロンティア研究センター, 特任准教授 (80402791) ; 大倉 永也 大阪大学, 免疫学フロンティア研究センター, 特任准教授 (20300949) ; 西川 博嘉 大阪大学, 免疫学フロンティア研究センター, 特任准教授 (10444431) ; 伊藤 能永 京都大学, 再生医科学研究所, 助教 (60614013)
• Keywords: FOXP3 / 制御性T細胞 / エピゲノム / Tリンパ球 / T細胞抗原レセプター / 免疫制御

Research Abstract

本年度、制御性T細胞(Regulatory T cell、以下Tregと略)の発生、および機能におけるエピゲノム変化について解析した。Tregは転写因子Foxp3を特異的に発現するが、Foxp3の発現のみではTregに特有な遺伝子群(例えば、Helios、Eos)の発現、また抑制機能の発揮には不十分である。この不十分性を補完する重要な因子はTreg特異的なエピゲノム変化である可能性を探索した。まずゲノム全般についてメチル化領域を検索し、Treg特異的脱メチル化部位を決定した。次に、Foxp3を発現しないがFoxp3レポーター分子を発現するマウスを作製し、Foxp3とTreg特異的脱メチル化の関係を解析したところ、Helios、Eosなどの遺伝子は、Foxp3に依存しないがエピゲノム変化に依存すること、また、Foxp3発現とTreg特異的エピゲノム変化は独立して起こる事象であることを見出した。さらに、どちらの事象もT細胞抗原レセプター(TCR)を介する刺激によって惹起されるとの結果を得た。即ち、TCRトランスジェニックマウスを用いて、胸腺でのTregの発生に必要な強度のTCR刺激が供されると、胸腺TregにTreg型遺伝子脱メチル化の誘導を確認した。TCRを介する刺激が弱いTCRトランスジェニックマウスでは脱メチル化は起こらなかった。さらに、通常のT細胞を用いた場合には、慢性的なTCR刺激によって、部分的に、このような脱メチル化を惹起できた。これらの結果から、機能的にまた表現型として安定なTregを誘導するためには、Foxp3の発現のみではなく、Treg特異的エピゲノム変化を誘導することの重要性が明らかとなった。この知見は、ヒトのTregを標的とした免疫応答制御法の開発に重要である。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

本研究課題では、制御性T細胞の発生、機能における分子的機序の解明を目的とする。本年度の成果、即ち、制御性T細胞特異的エピゲノム変化の発見と解析は、転写因子とエピゲノム変化が相まってリンパ球の細胞系譜の決定、機能の安定性の維持に働くことを示す良いモデルを提供できたと考える。

Strategy for Future Research Activity

本研究課題では、引き続き、転写因子Foxp3の機能と制御性T細胞特異的エピゲノム変化の二つの研究を、平行して遂行していく。また、これまでの成果に基づき、ヒト制御性T細胞の発生、機能の分子的基礎についても研究を進める。特に、制御性T細胞が癌免疫を抑制する作用について、その分子機構の解析と抑制解除の方法を探る。

Research Products

• [Journal Article] Differential effects of inhibition of bone morphogenic protein (BMP) signalling on T-cell activation and differentiation (2012)
  • Author(s): Yoshioka, Y., Ono, M., Osaki, M., Konishi, I., Sakaguchi, S.
  • Journal Title: Eur J Immunol Volume: 42 Pages: 749-759
• [Journal Article] A Novel Model of Rheumatoid Arthritis-Associated Interstitial Lung Disease in SKG Mice (2012)
  • Author(s): Keith, R. C., Powers, J. L., Redente, E. F., Sergew, A., Martin, R. J., Gizinski, A., Holers, V. M., Sakaguchi, S., Riches, D. W
  • Journal Title: Exp Lung Res Volume: 38 Pages: 55-66
  • DOI: 10.3109
  • Peer Reviewed
• [Journal Article] Re-establishing immunological self-tolerance in autoimmune disease (2012)
  • Author(s): Sakaguchi, S., Powrie, F., Ransohoff, R. M
  • Journal Title: Nat Med Volume: 18 Pages: 54-58
  • Peer Reviewed
• [Journal Article] Cancer/testis antigens are novel targets of immunotherapy for adult T-cell leukemia/lymphoma (2012)
  • Author(s): Nishikawa, H., Maeda, Y., Ishida, T., Gnjatic, S., Sato, E., Mori, F., Sugiyama, D., Ito, A., Fukumori, Y., Utsunomiya, A., Inagaki, H., Old, L. J., Ueda, R., and Sakaguchi, S
  • Journal Title: Blood Volume: 119 Pages: 3097-3104
  • DOI: 10.1182
  • Peer Reviewed
• [Journal Article] Intracellular tumor-associated antigens represent effective targets for passive immunotherapy (2012)
  • Author(s): Noguchi, T., Kato, T., Wang, L., Maeda, Y., Ikeda, H., Sato, E., Knuth, A., Gnjatic, S., Ritter, G., Sakaguchi, S., Old, L. J., Shiku, H., and Nishikawa, H
  • Journal Title: Cancer Res Volume: 72 Pages: 1672-1682
  • DOI: 10.1158
  • Peer Reviewed
• [Journal Article] T-cell receptor signaling and the pathogenesis of autoimmune arthritis : insights from mouse and man (2012)
  • Author(s): Sakaguchi, S., Benham, H., Cope, A.P., Thomas, R.
  • Journal Title: Immunol Cell Biol Volume: 90 Pages: 277-87
  • Peer Reviewed
• [Journal Article] T.Factors affecting operational tolerance after pediatric living-donor liver transplantation : impact of early post-transplant events and HLA match (2012)
  • Author(s): Ohe, H., Waki, K., Yoshitomi, M., Morimoto, T., Nafady-Hego, H., Satoda, N., Li, Y., Zhao, X., Sakaguchi, S., Uemoto, S., Bishop, G.A., Koshiba, T.
  • Journal Title: Transpl Int Volume: 25 Pages: 97-106
  • Peer Reviewed
• [Journal Article] The long-term survival potential of mature T lymphocytes is programmed during development in the thymus (2012)
  • Author(s): Sinclair, C, Saini, M., van der Loeff, I.S., Sakaguchi, S., Seddon, B.
  • Journal Title: Sci Signal Volume: 4 Pages: (199) : ra77
  • Peer Reviewed
• [Journal Article] Two modes of immune suppression by Foxp3(十) regulatory T cells under inflammatory or non-inflammatory conditions (2012)
  • Author(s): Yamaguchi, T., Wing, J.B., Sakaguchi, S.
  • Journal Title: Semin Immunol Volume: 23 Pages: 424-430
  • Peer Reviewed
• [Journal Article] Thymus, innate immunity and autoimmune arthritis : interplay of gene and environment (2012)
  • Author(s): Sakaguchi, S., Tanaka, S., Tanaka, A., Ito, Y., Maeda, S., Sakaguchi, N., Hashimoto, M.
  • Journal Title: FEBS Lett Volume: 585 Pages: 3633-3639
  • Peer Reviewed
• [Journal Article] FOXP3(+) regulatory T cells : control of FOXP3 expression by pharmacological agents (2012)
  • Author(s): Ohkura, N., Hamaguchi, M., Sa kaguchi, S.
  • Journal Title: Trends Pharmacol.Sci Volume: 32 Pages: 158-66
  • Peer Reviewed
• [Journal Article] SLAP Deficiency Enhances Number and Function of Tregs Preventing Chronic Autoimmune Arthritis in SKG Mice (2012)
  • Author(s): Peterson, L.K., Shaw, L.A., Joetham, A., Sakaguchi, S., Gelf, E.W., Dragone, L.L.
  • Journal Title: J.Immunol. Volume: 186 Pages: 2273-2281
  • Peer Reviewed
• [Journal Article] Cell-autonomous and -nonautonomous functions of CTLA-4 for negative control of immune responses (2011)
  • Author(s): Wing, K., Yamaguchi, T, Sakaguchi, S.
  • Journal Title: Trends Immunol Volume: 32 Pages: 428-433
  • Peer Reviewed
• [Journal Article] Damping by depletion (2011)
  • Author(s): Sakaguchi, S., Wing K.
  • Journal Title: Science Volume: 332 Pages: 542-543
  • Peer Reviewed
• [Journal Article] Maturation of effector regulatory T cells (2011)
  • Author(s): Ohkura, N., Sakaguchi, S.
  • Journal Title: Nat Immunol Volume: 12 Pages: 283-284
  • Peer Reviewed
• [Journal Article] TCR diversity and Treg cells, sometimes more is more (2011)
  • Author(s): Wing, J.B., Sakaguchi, S.
  • Journal Title: Eur J Immunol Volume: 41 Pages: 3097-3100
  • Peer Reviewed
• [Journal Article] Histological changes in chronic autoimmune SKG-arthritis evaluated by quantitative three-dimensional stereological estimators (2011)
  • Author(s): Keller, K.K., Stengaard-Pedersen, K., Dagnass-Hansen, F., Nyengaard, J.R., Sakaguchi, S., Hauge, E.M.
  • Journal Title: Clin.Exp.Rheumatol Volume: 29 Pages: 536-43
  • Peer Reviewed
• [Journal Article] Pillars Article : Immunologic Self-Tolerance Maintained by Activated T Cells Expressing IL-2 Receptor α-Chains (CD25). Breakdown of a Single Mechanism of Self-Tolerance Causes Various Autoimmune Diseases (2011)
  • Author(s): Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., Toda, M.
  • Journal Title: J.Immunol Volume: 186 Pages: 3808-21
  • Peer Reviewed
• [Journal Article] Minimal but essential doses of immunosuppression : A more realistic approach to improve long-term outcomes for pediatric living-donor liver transplantation (2011)
  • Author(s): Ohe, H., Li, Y, Nafady-Hego, H., Kayo, W., Sakaguchi, S., Wood, K., Calne, R., Uemoto, S., Koshiba, T.
  • Journal Title: Transplantation Volume: 91 Pages: 808-810
  • Peer Reviewed
• [Journal Article] HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo (2011)
  • Author(s): Satou, Y., Yasunaga, J., Zhao, T., Yoshida, M., Miyazato, P., Takai, K., Shimizu, K., Ohshima, K., Green, P.L., Ohkura, N., Yamaguchi, T., Ono, M., Sakaguchi, S., Matsuoka, M.
  • Journal Title: PLoS Pathog Volume: 7(2) Pages: e1001274
  • Peer Reviewed
• [Journal Article] Human FoxP3(+) regulatory T cells in systemic autoimmune diseases (2011)
  • Author(s): Miyara, M., Gorochov, G., Ehrenstein, M., Musset, L., Sakaguchi, S., Amoura, Z.
  • Journal Title: Autoimmun.Rev Volume: 10 Pages: 744-755
  • Peer Reviewed
• [Journal Article] FoxP3+CD4+ regulatory T cells : their knowns and unknowns (2011)
  • Author(s): Miyara, M., Sakaguchi, S.
  • Journal Title: Immunol.Cell.Biology Volume: 89 Pages: 346-351
  • Peer Reviewed
• [Journal Article] CSF-1-dependent red pulp macrophages regulate CD4 T cell responses (2011)
  • Author(s): Kurotaki, D., Kon, S., Bae, K., Ito, K., Matsui, Y., Nakayama, Y., Kanayama, M., Kimura, C., Narita, Y., Nishimura, T., Iwabuchi, K., Mack, M., van Rooijen, N., Sakaguchi, S., Uede, T., Morimoto, J.
  • Journal Title: J.Immunol Volume: 186 Pages: 2229-2237
  • Peer Reviewed
• [Journal Article] Stimulation of the glucocorticoid-induced TNF receptor family-related receptor on CD8 T cells induces protective and high-avidity T cell responses to tumor-specific antigens (2011)
  • Author(s): Cote, A.L., Zhang, P., O'Sullivan, J.A., Jacobs, V.L., Clemis, C.R., Sakaguchi, S., Guevara-Patino, J.A., Turk, M.J.
  • Journal Title: J.Immunol Volume: 186 Pages: 275-283
  • Peer Reviewed
• [Journal Article] Regulatory T cells : history and perspective (2011)
  • Author(s): Sakaguchi, S.
  • Journal Title: Methods in Molecular Biology Volume: 77 Pages: 1-13
  • Peer Reviewed
• [Presentation] Molecular basis of regulatory T cells development and their functional stability (2012)
  • Author(s): Shimon Sakaguchi
  • Organizer: Centre for Immune Regulation University of Oslo
  • Place of Presentation: Grand Hotel (Norway)(招待講演)
  • Year and Date: 2012-03-30
• [Presentation] Molecular basis of regulatory T cells development and their functional stability (2012)
  • Author(s): Shimon Sakaguchi
  • Organizer: Helmholtz Centre for Infection Research
  • Place of Presentation: Braunschweig (Germany)(招待講演)
  • Year and Date: 2012-03-28
• [Presentation] Treg development and function (2012)
  • Author(s): Shimon Sakaguchi
  • Organizer: International Symposium Migration and Regulation : Managing immune-mediated diseases
  • Place of Presentation: Berlin-Brandenburgische Akademie der Wissenschaften, Berlin (Germany)(招待講演)
  • Year and Date: 2012-03-26
• [Presentation] Molecular basis of regulatory T cells development and their functional stability (2012)
  • Author(s): Shimon Sakaguchi
  • Organizer: Max Planck Institute of Neurobiology
  • Place of Presentation: MPI fur Neurobiologie (Germany)(招待講演)
  • Year and Date: 2012-03-22
• [Presentation] Roles of concurrent epigenetic conversion and Foxp3 expression for the development of regulatory T cells (2012)
  • Author(s): Shimon Sakaguchi
  • Organizer: Winter School 2012 on Advanced Immunology
  • Place of Presentation: 淡路夢舞台(兵庫)(招待講演)
  • Year and Date: 2012-01-19
• [Presentation] Regulatory T cells for Immune Regulation (2012)
  • Author(s): Shimon Sakaguchi
  • Organizer: International symposium : Infection, immunity and cacer
  • Place of Presentation: 芝蘭会館(京都)(招待講演)
  • Year and Date: 2012-01-16
• [Presentation] 遺伝子変異と発病の間のブラックボックス解明のために構造生物学ができること (2012)
  • Author(s): 坂口志文
  • Organizer: 日本学術会議公開シンポジウム
  • Place of Presentation: 日本学術会議大講堂(東京)(招待講演)
  • Year and Date: 2012-01-09
• [Presentation] Regulatory T Cells for the control of physiological and pathological immune responses (2011)
  • Author(s): Shimon Sakaguchi
  • Organizer: 6^<th> European Workshop on Immune-Mediated Inflammatory Diseases
  • Place of Presentation: Radisson Blu(France)(招待講演)
  • Year and Date: 20111123-20111125
• [Presentation] 制御性T細胞による免疫応答制御 (2011)
  • Author(s): 坂口志文
  • Organizer: 第61回日本アレルギー学会
  • Place of Presentation: グランドプリンスホテル新高輪(東京)(招待講演)
  • Year and Date: 20111110-20111112
• [Presentation] Regulatory T Cells for immunological tolerance and immune homeostasis (2011)
  • Author(s): Shimon Sakaguchi
  • Organizer: 8^<th> Nestle International Nutrition Symposium Nutrition & the Immune System
  • Place of Presentation: Lausanne (Switzerland)(招待講演)
  • Year and Date: 20111019-20111021
• [Presentation] 制御性T細胞による免疫応答制御 (2011)
  • Author(s): 坂口志文
  • Organizer: 第47回日本移植学会総会
  • Place of Presentation: 仙台国際センター(福島県)(招待講演)
  • Year and Date: 20111004-20111006
• [Presentation] Autoimmune arthritis caused by systemic alteration of the T cell immune system (2011)
  • Author(s): Shimon Sakaguchi
  • Organizer: 39^<th> Congress of the German Society of Rheumatology
  • Place of Presentation: ICM&ndash InternationalCongrees Centre Munich( Germany)(招待講演)
  • Year and Date: 20110831-20110903
• [Presentation] 制御性T細胞による免疫応答制御 (2011)
  • Author(s): 坂口志文
  • Organizer: 日本免疫学会第13回免疫サマースクール
  • Place of Presentation: ラフォーレ蔵王リゾート&スパ(山形)(招待講演)
  • Year and Date: 20110801-20110804
• [Presentation] 制御性T細胞による腫瘍免疫応答の制御 (2011)
  • Author(s): 坂口志文
  • Organizer: 第15回日本がん免疫学会総会
  • Place of Presentation: 千里ライフサイエンスセンター(大阪)(招待講演)
  • Year and Date: 20110630-20110701
• [Presentation] 制御性T細胞による免疫応答制御 (2011)
  • Author(s): 坂口志文
  • Organizer: 第21回日本サイトメトリ-学会学術集会
  • Place of Presentation: 京都市国際交流会館(京都)(招待講演)
  • Year and Date: 20110625-20110626
• [Presentation] Therapeutic modalities-future prospects (2011)
  • Author(s): Shimon Sakaguchi
  • Organizer: The Herrenhausen Symposium on Autoimmunity
  • Place of Presentation: Kloster Seeon, (Germany)(招待講演)
  • Year and Date: 20110620-20110623
• [Presentation] Regulatory T Cells for immunological self-tolerance and immune homeostasis (2011)
  • Author(s): Shimon Sakaguchi
  • Organizer: 14^<th> Australasian Autoimmunity Workshop
  • Place of Presentation: The University of Queens land(Australia)(招待講演)
  • Year and Date: 20110518-20110519
• [Presentation] TCR signaling and autoimmune arthritis (2011)
  • Author(s): Shimon Sakaguchi
  • Organizer: Australian Rheumatology Association 52^<nd> Annual Scientific Meeting
  • Place of Presentation: Brisbane Convention and Exhibition Centre (Australia)(招待講演)
  • Year and Date: 20110514-20110517
• [Presentation] T cell signaling, regulatory T cells, and self-tolerance (2011)
  • Author(s): Shimon Sakaguchi
  • Organizer: Advances in Targeted Therapies
  • Place of Presentation: Hotel Radisson Blu (Croatia)(招待講演)
  • Year and Date: 20110406-20110410
• [Presentation] Induction of tumor immunity by targeting regulatory T cells (2011)
  • Author(s): Shimon Sakaguchi
  • Organizer: Joint Symposium of Seoul St.Mary's Hop, Osaka Univ.Postech
  • Place of Presentation: Seoul St, Mary's Hospital (Korea)(招待講演)
  • Year and Date: 2011-12-19
• [Presentation] Control of Immune Responses by Regulatory T Cells (2011)
  • Author(s): Shimon Sakaguchi
  • Organizer: 10^<th> Faculty Research Symposium Frontiers in Biomedical Research
  • Place of Presentation: Cheung Kung Hai Conference Centre (China)(招待講演)
  • Year and Date: 2011-12-09
• [Presentation] Regulatory T cells for immune tolerance and homeostasis (2011)
  • Author(s): Shimon Sakaguchi
  • Organizer: Institut Federatif de Recherche Bio-Medicale de Toulouse INSERM
  • Place of Presentation: Toulouse(France)(招待講演)
  • Year and Date: 2011-11-22
• [Presentation] Regulatory T cells for immune tolerance and homeostasis (2011)
  • Author(s): Shimon Sakaguchi
  • Organizer: nstitut Pasteur, Immunology Department Seminar
  • Place of Presentation: Paris(France)(招待講演)
  • Year and Date: 2011-11-21
• [Presentation] 制御性T細胞による免疫応答制御 (2011)
  • Author(s): 坂口志文
  • Organizer: 自治医科大学大学院特別セミナー
  • Place of Presentation: 自治医科大学(栃木)(招待講演)
  • Year and Date: 2011-09-27
• [Presentation] 制御性T細胞による免疫応答制御 (2011)
  • Author(s): 坂口志文
  • Organizer: 東京大学医科学研究所大学院特別セミナー
  • Place of Presentation: 東京大学(東京)(招待講演)
  • Year and Date: 2011-09-12
• [Presentation] 制御性T細胞による免疫応答制御 (2011)
  • Author(s): 坂口志文
  • Organizer: 久留米大学大学院講義
  • Place of Presentation: 久留米大学(福岡)(招待講演)
  • Year and Date: 2011-06-01
• [Presentation] T細胞シグナル、制御性T細胞、自己免疫病 (2011)
  • Author(s): 坂口志文
  • Organizer: 東京大学大学院GCOEセミナー
  • Place of Presentation: 東京大学(東京)(招待講演)
  • Year and Date: 2011-05-26
• [Presentation] 制御性T細胞による免疫応答制御 (2011)
  • Author(s): 坂口志文
  • Organizer: 第62回未来医療セミナー
  • Place of Presentation: 大阪大学医学部講義棟C講堂(大阪)(招待講演)
  • Year and Date: 2011-04-20