エピジェネティック改変による安定化制御性Ｔ細胞の誘導と免疫疾患への応用

• Project/Area Number: 15J03260
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 国内
• Research Field: Immunology
• Research Institution: Keio University
• Principal Investigator: 中司 寛子 慶應義塾大学, 医学部, 助教
• Project Period (FY): 2015-04-24 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 制御性T細胞 / エピジェネティクス / 自己免疫疾患

Outline of Annual Research Achievements

I. T細胞におけるTETの機能解明
T細胞特異的Tet2/3両欠損(DKO)マウスに抗生物質を投与したところ、脾・リンパ節腫脹等の症状は緩和されたことから、DKOマウスは腸内細菌によるT細胞受容体 (TCR)刺激が過増殖の原因であると考えられた。また、DKOマウスでは大腸粘膜固有層におけるTregの割合が減少し、Th17細胞は増加していた。さらにDKOマウスのTregの大半が胸腺由来TregのマーカーであるHeliosを高発現したことから、Tetは末梢におけるTreg/Th17分化に重要であることが示唆された。次にDKOマウスをRag2-/-OT-IIトランスジェニックマウス(Rag2-/-OT-II)背景で作製した。DKO/Rag2-/-OT-IIマウスは脾・リンパ節腫脹等の症状を自然発症せず、抗原となるOVAの投与により発症が認められた。さらに、OVA投与後、Rag2-/-OT-IIマウスでは末梢リンパ器官においてTregが誘導されていたのに対し、DKO/Rag2-/-OT-IIマウスではTregの誘導は見られず、Th17細胞の誘導が見られたことから、Tetが末梢におけるT細胞の過増殖およびTreg/Th17分化に重要であることが示された。
II. 制御性T細胞におけるTETの機能解明
TET2/3欠損TregをRag2-/-マウスに移入したところ、Foxp3発現が低下し、移入したTregはIL-17を産生するexFoxp3細胞に転換したことから、TetはTregの安定性に重要であることが示唆された。次に、TregにおけるDNAメチル化状態とオープンクロマチン状態を解析したところ、Tet欠損TregではFoxp3遺伝子の約5kb上流領域に強いメチル化とATACピークの消失が認められ、本領域におけるFoxp3の安定性への寄与が示唆された。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Inhibition of Nr4a receptors enhances anti-tumor immunity by breaking Treg-mediated immune tolerance. (2018)
  • Author(s): Hibino S, Chikuma S, Kondo T, Ito M, Nakatsukasa H, Omata-Mise S, Yoshimura A
  • Journal Title: Cancer Res Volume: Epub Issue: 11 Pages: 3027-3040
  • DOI: 10.1158/0008-5472.can-17-3102
  • Peer Reviewed / Open Access
• [Journal Article] Generation of alloantigen-specific induced-Treg stabilized by vitamin C treatment and its application for prevention of acute graft versus host disease model (2017)
  • Author(s): Hidenori Kasahara, Taisuke Kondo, Hiroko Nakatsukasa, Shunsuke Chikuma, Minako Ito, Makoto Ando, Yutaka Kurebayashi, Takashi Sekiya, Taketo Yamada, Shinichiro Okamoto, Akihiko Yoshimura
  • Journal Title: International Immunology Volume: 29 Issue: 10 Pages: 457-469
  • DOI: 10.1093/intimm/dxx060
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Improvement of Foxp3 stability through CNS2 demethylation by TET enzyme induction and activation (2017)
  • Author(s): Someya Kazue、Nakatsukasa Hiroko、Ito Minako、Kondo Taisuke、Tateda Kenn-ichi、Akanuma Takashi、Koya Ikuko、Sanosaka Tsukasa、Kohyama Jun、Tsukada Yu-ichi、Takamura-Enya Takeji、Yoshimura Akihiko
  • Journal Title: International Immunology Volume: 29 Issue: 8 Pages: 365-375
  • DOI: 10.1093/intimm/dxx049
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Negative Regulation of Cytokine Signaling in Immunity (2017)
  • Author(s): Yoshimura Akihiko、Ito Minako、Chikuma Shunsuke、Akanuma Takashi、Nakatsukasa Hiroko
  • Journal Title: Cold Spring Harbor Perspectives in Biology Volume: - Issue: 7 Pages: a028571-a028571
  • DOI: 10.1101/cshperspect.a028571
  • Peer Reviewed
• [Journal Article] Induction and maintenance of regulatory T cells by transcription factors and epigenetic modifications (2017)
  • Author(s): Iizuka-Koga Mana、Nakatsukasa Hiroko、Ito Minako、Akanuma Takashi、Lu Qianjin、Yoshimura Akihiko
  • Journal Title: Journal of Autoimmunity Volume: 83 Pages: 113-121
  • DOI: 10.1016/j.jaut.2017.07.002
  • Peer Reviewed
• [Journal Article] SOCS1 Is a Key Molecule That Prevents Regulatory T Cell Plasticity under Inflammatory Conditions. (2017)
  • Author(s): Takahashi R, Nakatsukasa H, Shiozawa S, Yoshimura A.
  • Journal Title: J Immunol. Volume: 199 Issue: 1 Pages: 149-158
  • DOI: 10.4049/jimmunol.1600441
  • Peer Reviewed
• [Journal Article] Stabilization of Foxp3 expression by CRISPR-dCas9-based epigenome editing in mouse primary T cells. (2017)
  • Author(s): Okada M, Kanamori M, Someya K, Nakatsukasa H and Yoshimura A.
  • Journal Title: Epigenetics & Chromatin Volume: 印刷中 Issue: 1 Pages: 24-24
  • DOI: 10.1186/s13072-017-0129-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Notch-mediated conversion of activated T cells into stem cell memory-like T cells for adoptive immunotherapy. (2017)
  • Author(s): Kondo T, Morita R, Okuzono Y, Nakatsukasa H, Sekiya T, Chikuma S, Shichita T, Kanamori M, Kubo M, Koga K, Miyazaki T, Kassai Y, and Yoshimura A.
  • Journal Title: Nat Commun. Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Role of ATP as a Key Signaling Molecule Mediating Radiation-Induced Biological Effects. (2017)
  • Author(s): Kojima S, Ohshima Y, Nakatsukasa H, Tsukimoto M.
  • Journal Title: Dose Response. Volume: 15 Issue: 1 Pages: 1-11
  • DOI: 10.1177/1559325817690638
  • Peer Reviewed / Open Access
• [Journal Article] Induced Regulatory T Cells: Their Development, Stability, and Applications. (2016)
  • Author(s): Kanamori M, Nakatsukasa H, Okada M, Lu Q, Yoshimura A.
  • Journal Title: Trends Immunol. Volume: 37 Issue: 11 Pages: 803-811
  • DOI: 10.1016/j.it.2016.08.012
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Roles of transcription factors and epigenetic modifications in differentiation and maintenance of regulatory T cells. (2016)
  • Author(s): Sekiya T, Nakatsukasa H, Lu Q, and Yoshimura A.
  • Journal Title: Microbes Infect. Volume: 18 Issue: 6 Pages: 378-386
  • DOI: 10.1016/j.micinf.2016.02.004
  • Peer Reviewed / Int'l Joint Research
• [Presentation] TET2 and TET3 regulate stability and homeostasis of regulatory T cells. (2017)
  • Author(s): Nakatsukasa H and Yoshimura A.
  • Organizer: 第19回武田科学振興財団生命科学シンポジウム
  • Place of Presentation: 武田薬品研修所（大阪府吹田市）
  • Year and Date: 2017-01-20
  • Int'l Joint Research
• [Presentation] TET2 and TET3 regulate Treg stability through Treg-specific DNA demethylation. (2017)
  • Author(s): Nakatsukasa H and Yoshimura A.
  • Organizer: Keystone Symposia on Molecular and Cellular Biology
  • Place of Presentation: タオス（アメリカ）
  • Year and Date: 2017-01-09
  • Int'l Joint Research
• [Presentation] TET2 and TET3 regulate helper T cell differentiation in the periphery. (2017)
  • Author(s): Nakatsukasa H and Yoshimura A.
  • Organizer: Cytokine2017
  • Int'l Joint Research
• [Presentation] 制御性T細胞におけるDNA脱メチル化酵素TETの機能解明 (2017)
  • Author(s): 中司寛子、吉村昭彦
  • Organizer: 第32回自己免疫研究会
• [Presentation] TET2 and TET3 regulate stability and function of regulatory T cells (2017)
  • Author(s): Nakatsukasa H and Yoshimura A.
  • Organizer: IMMUNOLOGY 2017
  • Int'l Joint Research
• [Presentation] TET2 and TET3 play essential roles in Treg-specific DNA demethylation and Treg stability. (2016)
  • Author(s): Nakatsukasa H and Yoshimura A.
  • Organizer: International Congress of Immunology 2016
  • Place of Presentation: メルボルン（オーストラリア）
  • Year and Date: 2016-08-21
  • Int'l Joint Research
• [Presentation] TET2 and TET3 play essential roles in Treg-specific DNA demethylation and Treg stability (2016)
  • Author(s): 中司寛子
  • Organizer: International Congress of Immunology 2016
  • Place of Presentation: メルボルン（オーストラリア）
  • Year and Date: 2016-08-21
  • Int'l Joint Research
• [Presentation] 制御性T細胞のDNA脱メチル化による制御 (2016)
  • Author(s): 中司寛子、吉村昭彦
  • Organizer: 第１回Clinical Immunology/Inflammation Seminar in Shinanomachi
  • Place of Presentation: 慶應義塾大学（東京都新宿区）
  • Year and Date: 2016-07-09
• [Presentation] 制御性T細胞のヒドロキシメチル化による制御 (2016)
  • Author(s): 中司寛子
  • Organizer: 第２回病因研究会別府シンポジウム
  • Place of Presentation: 別府湾ロイヤルホテル（大分県速見郡）
  • Year and Date: 2016-02-06
• [Presentation] T細胞特異的Tet2,Tet3遺伝子欠損マウスの解析 (2016)
  • Author(s): 中司寛子
  • Organizer: AMED-CREST「エピゲノム研究に基づく診断・治療へ向けた新技術の創出」研究開発領域第５回領域会議
  • Place of Presentation: メルパルク熊本（熊本県熊本市）
  • Year and Date: 2016-01-06
• [Book] 臨床免疫・アレルギー科 (2017)
  • Author(s): 中司寛子
  • Total Pages: 6
  • Publisher: 科学評論社
• [Book] 実験医学増刊 (2016)
  • Author(s): 吉村昭彦、岡田匡央、金森光広、中司寛子
  • Total Pages: 6
  • Publisher: 羊土社
• [Book] 臨床免疫・アレルギー科 (2016)
  • Author(s): 中司寛子、金森光広、岡田匡央、吉村昭彦
  • Total Pages: 7
  • Publisher: 科学評論社