The regulation of B cell tolerance by DNA demethylase, Ten-eleven translocation

• Project/Area Number: 19K08883
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Kyushu University
• Principal Investigator: Tanaka Shinya 九州大学, 生体防御医学研究所, 准教授 (80462703)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 末梢寛容 / 自己免疫疾患 / 免疫寛容 / Tet分子 / DNA demethylation / Self tolerance / B cells

Outline of Research at the Start

世界人口の数パーセントは、なんらかの自己免疫疾患に罹患していると報告されており、自己寛容の破綻がその直接的な原因となるが、その根本的治療方法は確立されていない。また、近年、抗ガン治療に用いられている免疫チェックポイント阻害薬は、作用機序において自己寛容破綻を促進してしまうため、これら疾患を制御するには、自己寛容の分子メカニズムを明らかにする必要がある。本研究では、自己免疫疾患の発症において近年注目を集めているB細胞に焦点をあて、DNAメチル化によっていかに自己寛容が制御されるかについて分子レベルでの解明を目指す。

Outline of Final Research Achievements

It has been suggested that autoimmune diseases are induced by defect of epigenetic gene regulations which may be affected by environmental factors exposing human body during life course. However, it remains unclear how dysregulation of epigenetics causes autoimmune diseases. In this current study, B cell-specific deletion of Ten-eleven translocation (Tet), which acts as a DNA demethylase, was causative of an activation of self-reactive B cells which resulted in dysregulated T cell activation via antigen-mediated cell-cell interaction. It turned out autoimmune disease pathogenesis. These findings suggest that Tet molecules play a critical role in induction and/or maintenance of B cell peripheral tolerance. Also, this study indicates the defective epigenetic control could be a direct cause of an induction of autoimmune diseases.

Academic Significance and Societal Importance of the Research Achievements

自己免疫疾患は、ライフコース後期に頻発する炎症性疾患であり、その罹患率は、さらに上昇するものと考えられる。最近、遺伝要因だけでなく、環境要因によるエピゲノムの乱れがその発症に寄与する可能性が示唆されるようになった。しかしながら、両者の直接的関係は全く明らかではない。本研究において、DNA脱メチル化酵素の機能不全を切り口として、自己免疫疾患発症におけるエピゲノム制御の直接な役割を示したことで、今後、エピゲノム制御という観点から自己免疫疾患制御についてさらなる知見がもたらされるものと考えられ、ひいては新たは疾患治療戦略につながることが期待される。

Research Products

• [Journal Article] Silencing and activating anergic B cells (2021)
  • Author(s): Shinya Tanaka, Wataru Ise, Yoshihiro Baba, Tomohiro Kurosaki
  • Journal Title: Immunological reviews Volume: 307 Issue: 1 Pages: 43-52
  • DOI: 10.1111/imr.13053
  • Peer Reviewed
• [Journal Article] Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity (2020)
  • Author(s): Tanaka, S. Ise, W. Inoue, T. Ito, A. Ono, C. Shima, Y. Sakakibara, S. Nakayama, M. Fujii, K. Miura, I. Sharif, J. Koseki, H. Koni, P. A. Raman, I. Li, Q. Z. Kubo, M. Fujiki, K. Nakato, R. Shirahige, K. Araki, H. Miura, F. Ito, T. Kawakami, E. Baba, Y. Kurosaki, T.
  • Journal Title: Nature Immunology Volume: 21 Issue: 8 Pages: 950-961
  • DOI: 10.1038/s41590-020-0700-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tet DNA demethylase is required for plasma cell differentiation by controlling expression levels of IRF4 (2020)
  • Author(s): Fujii, K. Tanaka, S. Hasegawa, T. Narazaki, M. Kumanogoh, A. Koseki, H. Kurosaki, T. Ise, W.
  • Journal Title: International Immunology Volume: 32 Issue: 10 Pages: 683-690
  • DOI: 10.1093/intimm/dxaa042
  • Peer Reviewed / Open Access
• [Presentation] Role of Ten-eleven translocation (Tet) in B cell self-tolerance (2021)
  • Author(s): Shinya Tanaka
  • Organizer: The federation of immunological societies of Asia-Oceania (FIMSA) 2021
  • Int'l Joint Research / Invited
• [Presentation] Role of Ten-eleven translocation (Tet) in B cell self-tolerance (2021)
  • Author(s): Shinya Tanaka, Wataru Ise, Tomohiro Kurosaki, Yoshihiro Baba
  • Organizer: The 50th annual meeting of the Japanese society for immunology
• [Presentation] Role of Ten eleven translocation in B cell self tolerance (2020)
  • Author(s): Shinya Tanaka
  • Organizer: The 15h International Symposium of the Institute Network for Biomedical Sciences
  • Int'l Joint Research / Invited
• [Presentation] Ten-eleven translocation (Tet) in B cells prevents autoimmunity (2019)
  • Author(s): 田中伸弥
  • Organizer: 日本免疫学会総会
• [Book] Advances in Experimental Medicine and Biology (Chapter 4 of B Cell Receptor Signaling) (2020)
  • Author(s): Shinya Tanaka
  • Publisher: Springer International Publishing