The role of DNA demethylase TET in T cell function and differentiation.

• Project/Area Number: 18K15198
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Keio University
• Principal Investigator: NAKATSUKASA Hiroko 慶應義塾大学, 医学部(信濃町), 助教 (90749334)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: DNAメチル化 / 制御性T細胞 / エピジェネティクス / 自己免疫疾患 / TET / Tfh細胞 / 腸内細菌 / Th17細胞 / T細胞分化

Outline of Final Research Achievements

Ten-eleven translocation (TET) proteins regulate DNA methylation and gene expression. Previously we found that T cell-specific Tet2 and Tet3 double-knockout (Tet2f/fTet3f/fCd4-Cre; DKO) mice displayed splenomegaly and lymph adenopathy accompanied by uncontrolled activation of T cells which exhibited Th17- and/or follicular helper T (Tfh)-like phenotypes. In this study, we revealed that Tet2 and Tet3 regulate Treg/Th17 differentiation in periphery. Furthermore, DKO phenotypes were abrogated by treatment of antibiotics, especially by metronidazole, or restriction of TCR repertoire, suggesting the contribution of gut microbiota as intestinal antigen. We also revealed the involvement of upstream region of Foxp3 gene as Tet target region to regulate Treg stability. Thus, Tet plays important roles in T cell differentiation and function.

Academic Significance and Societal Importance of the Research Achievements

これまでヘルパーT細胞の分化機構に関しては急速に研究が進み、転写ネットワークによるヘルパーT細胞の分化機構については非常に多くの報告がなされているが、エピジェネティックな制御による可塑性、安定性についての研究は端緒についたばかりである。本研究ではDNA脱メチル化酵素TETがヘルパーT細胞分化の安定性と可塑性に関与することを明らかとしたが、今後さらに詳細な制御機構が解明されれば、免疫疾患、炎症性疾患やがんの新規治療法確立への応用が期待される。

Research Products

• [Journal Article] Loss of TET proteins in regulatory T cells promotes abnormal proliferation, Foxp3 destabilization, and IL-17 expression. (2019)
  • Author(s): Nakatsukasa H, Oda M, Yin J, Chikuma S, Ito M, Koga-Iizuka M, Someya K, Kitagawa Y, Ohkura N, Sakaguchi S, Koya I, Sanosaka T, Kohyama J, Tsukada YI, Yamanaka S, Takamura-Enya T, Lu Q, Yoshimura A
  • Journal Title: International immunology Volume: 31 Issue: 5 Pages: 335-347
  • DOI: 10.1093/intimm/dxz008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery (2019)
  • Author(s): Ito Minako、Komai Kyoko、Mise-Omata Setsuko、Iizuka-Koga Mana、Noguchi Yoshiko、Kondo Taisuke、Sakai Ryota、Matsuo Kazuhiko、Nakayama Takashi、Yoshie Osamu、Nakatsukasa Hiroko、Chikuma Shunsuke、Shichita Takashi、Yoshimura Akihiko
  • Journal Title: Nature Volume: 565 Issue: 7738 Pages: 246-250
  • DOI: 10.1038/s41586-018-0824-5
  • Peer Reviewed / Open Access
• [Journal Article] IL-6, IL-17 and Stat3 are required for auto-inflammatory syndrome development in mouse. (2018)
  • Author(s): Oike T, Kanagawa H, Sato Y, Kobayashi T, Nakatsukasa H, Miyamoto K, Nakamura S, Kaneko Y, Kobayashi S, Harato K, Yoshimura A, Iwakura Y, Takeuchi T, Matsumoto M, Nakamura M, Niki Y, Miyamoto T.
  • Journal Title: Sci Rep. Volume: - Issue: 1 Pages: 15783-15783
  • DOI: 10.1038/s41598-018-34173-5
  • Peer Reviewed / Open Access
• [Journal Article] Reprogramming of Th1 cells into regulatory T cells through rewiring of the metabolic status. (2018)
  • Author(s): Kanamori M, Nakatsukasa H, Ito M, Chikuma S, Yoshimura A.
  • Journal Title: Int Immunol. Volume: 30 Issue: 8 Pages: 357-373
  • DOI: 10.1093/intimm/dxy043
  • Peer Reviewed
• [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
• [Presentation] T細胞分化におけるDNA脱メチル化酵素Tetの機能解明 (2019)
  • Author(s): 中司寛子、吉村昭彦
  • Organizer: 大阪大学第13回若手研究フォーラム
• [Presentation] Gut microbiota mediate T cell senescence in Tet-deficient T cells. (2019)
  • Author(s): 中司寛子、吉村昭彦
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] Tet2 and Tet3 regulate helper T cell differentiation in the periphery. (2018)
  • Author(s): Hiroko Nakatsukasa, Akihiko Yoshimura
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] T細胞分化におけるDNA脱メチル化酵素Tetの機能解明 (2018)
  • Author(s): 中司寛子、吉村昭彦
  • Organizer: 第39回日本炎症・再生医学会