Understanding the mechanisms of the maintenance and invlution of thymus

• Project/Area Number: 15K19125
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Immunology
• Research Institution: Hokkaido University (2019); Kyoto University (2015-2018)
• Principal Investigator: Sekai Miho 北海道大学, 遺伝子病制御研究所, 特任助教 (50737533)
• Project Period (FY): 2015-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 胸腺 / 上皮細胞 / 幹細胞 / 上皮幹細胞 / コロニー形成能 / 免疫 / 胸腺上皮細胞 / コロニー / 胸腺上皮幹細胞

Outline of Final Research Achievements

The thymus is a central lymphoid organ essential for T-cell production. Within the thymus, medullary thymic epithelial cells (mTECs) play a crucial role in central T-cell tolerance. In this study, we have identified the stem cells for mTECs that restore functional medulla formation and prevent the development of autoimmune diseases throughout life-long upon transplantation. Furthermore, we demonstrate that the stem cell activity rapidly decreases soon after birth, while the activity is maintained in adult Rag2-deficient mice with impaired T-cell development.

Academic Significance and Societal Importance of the Research Achievements

本研究は、胸腺の機能的な髄質上皮細胞の産生、および、T細胞の中枢性の自己寛容を生涯にわたり維持しうる胸腺の髄質上皮幹細胞の存在をはじめて証明した。また、髄質上皮幹細胞の移植により、髄質の機能不全をともなう臓器特異的な自己免疫疾患の発症を抑制しうること、および、髄質上皮幹細胞の活性の制御機構の一端を明らかにすることができた。以上の結果は、胸腺および免疫系の維持や制御についての理解に繋がると考えられる。

Research Products

• [Journal Article] An improved clonogenic culture method for thymic epithelial cells (2019)
  • Author(s): Sekai Miho、Wang Jianwei、Minato Nagahiro、Hamazaki Yoko
  • Journal Title: Journal of Immunological Methods Volume: 467 Pages: 29-36
  • DOI: 10.1016/j.jim.2019.02.003
  • Peer Reviewed / Open Access
• [Journal Article] Clonogenic Culture of Mouse Thymic Epithelial Cells (2019)
  • Author(s): Sekai Miho、Wang Jianwei、Hamazaki Yoko
  • Journal Title: Methods Mol Biol. Volume: 2048 Pages: 143-153
  • DOI: 10.1007/978-1-4939-9728-2_15
  • ISBN: 9781493997275, 9781493997282
  • Peer Reviewed / Open Access
• [Journal Article] Hassall’s corpuscles with cellular-senescence features maintain IFNα production through neutrophils and pDC activation in the thymus (2018)
  • Author(s): Wang Jianwei、Sekai Miho、Matsui Takeshi、Fujii Yosuke、Matsumoto Mitsuru、Takeuchi Osamu、Minato Nagahiro、Hamazaki Yoko
  • Journal Title: International Immunology Volume: 31 Issue: 3 Pages: 127-139
  • DOI: 10.1093/intimm/dxy073
  • NAID: 120007164929
  • Peer Reviewed / Open Access
• [Journal Article] A human PSMB11 variant affects thymoproteasome processing and CD8+ T cell production (2017)
  • Author(s): Ohigashi I, Ohte Y, Setoh K, Nakase H, Maekawa A, Kiyonari H, Hamazaki Y, Sekai M, Sudo T, Tabara Y, Sawai H, Omae Y, Yuliwulandari R, Tanaka Y, Mizokami M, Inoue H, Kasahara M, Minato N, Tokunaga K, Tanaka K, Matsuda F, Murata S, Takahama Y.
  • Journal Title: JCI Insight Volume: 2 Issue: 10 Pages: 1-14
  • DOI: 10.1172/jci.insight.93664
  • NAID: 120006733720
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Physiologic Thymic Involution Underlies Age-Dependent Accumulation of Senescence-Associated CD4+T Cells (2017)
  • Author(s): Sato Kyosuke、Kato Aiko、Sekai Miho、Hamazaki Yoko、Minato Nagahiro
  • Journal Title: The Journal of Immunology Volume: 199 Issue: 1 Pages: 138-148
  • DOI: 10.4049/jimmunol.1602005
  • Peer Reviewed / Open Access
• [Journal Article] Medullary thymic epithelial stem cells: role in thymic epithelial cell maintenance and thymic involution (2016)
  • Author(s): Hamazaki Y, Sekai M, Minato N
  • Journal Title: Immunol Rev. Volume: 271 Issue: 1 Pages: 38-55
  • DOI: 10.1111/imr.12412
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Obesity accelerates T-cell senescence in visceral adipose tissue (2016)
  • Author(s): Shirakawa K, Yan X, Shinmura K, Endo J, Kataoka M, Katsumata Y, Yamamoto T, Anzai A, Isobe S, Yoshida N, Itoh H, Manabe I, Sekai M, Hamazaki Y, Fukuda K, Minato N, and Sano M.
  • Journal Title: J Clin Invest. Volume: 126 Issue: 12 Pages: 4626-4639
  • DOI: 10.1172/jci88606
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Relb acts downstream of medullary thymic epithelial stem cells and is essential for the emergence of RANK+ medullary epithelial progenitors. (2016)
  • Author(s): Baik S, Sekai M, Hamazaki Y, Jenkinson WE, Anderson G.
  • Journal Title: Eur J Immunol. Volume: - Issue: 4 Pages: 857-62
  • DOI: 10.1002/eji.201546253
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Thymopoiesis regulates the clonogenic activity of thymic epithelial cells (2018)
  • Author(s): Miho Sekai, Yoko Hamazaki, Nagahiro Minato
  • Organizer: 日本免疫学会学術集会
• [Presentation] Thymopoiesis regulates clonogenic activity of thymic epithelial cells (2017)
  • Author(s): Miho Sekai, Yoko Hamazaki, Nagahiro Minato
  • Organizer: 7th International Workshop of Kyoto T Cell Conference
  • Place of Presentation: 京都
  • Year and Date: 2017-03-13
  • Int'l Joint Research
• [Presentation] Identification and analysis of medullary thymic epithelial cells constituting Hassall’s corpuscles in the murine thymus (2017)
  • Author(s): Jianwei Wang, Miho Sekai, NAgahiro Minato, Yoko Hamazaki
  • Organizer: 7th International Workshop of Kyoto T Cell Conference
  • Place of Presentation: 京都
  • Year and Date: 2017-03-13
  • Int'l Joint Research