Analysis of the memory CD8 T-cell differentiaition via control of histone demethylation

• Project/Area Number: 17K08887
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Ehime Prefectural University of Health Science (2018-2019); Ehime University (2017)
• Principal Investigator: Yamada Takeshi 愛媛県立医療技術大学, 保健科学部, 教授 (40333554)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 免疫 / 感染症 / T細胞 / CD8 / メモリー / エピジェネティック制御 / CD8 T細胞 / メモリー分化 / Utx / 感染免疫 / CD8+T細胞 / ヒストン脱メチル化

Outline of Final Research Achievements

Although epigenetic changes play a critical role in T-cell differentiation and its function, the role of histone H3K27 methylation in the CD8+ T cell-dependent immune response remains unclear. We therefore analyzed T cell-specific Utx knockout (Utx KO) mice to determine the role of histone H3K27 demethylase in CD8+ T cells.
Wild-type (WT) and Utx KO mice were infected with Listeria to analyze the immune response of Ag-specific CD8+ T cells. Utx deficiency resulted in an increased number of Ag-specific CD8+ T cells upon secondary infection. These data suggest that Utx negatively controls the memory formation of Ag-stimulated CD8+ T cells by epigenetically regulating the gene expression.

Academic Significance and Societal Importance of the Research Achievements

長期免疫の獲得に重要な記憶（メモリー）T細胞分化の誘導は、感染症克服のための重要な研究課題となっている。実用的なワクチン開発を行う上で、メモリーT細胞分化メカニズムの理解は不可欠であるが、その分化を制御するエピジェネティック調節機構については、まだ明らかとなっていない。そこで本研究は、CD8 T細胞におけるヒストン脱メチル化酵素の役割に焦点を当てた解析を行い、エピジェネティック変化によるメモリーCD8 T細胞分化の制御メカニズムの一部を明らかにした。これらの成果は、エピジェネティック調節をすることで人為的にメモリーT細胞分化制御を行い、感染症に対する長期免疫を誘導できる可能性を秘めている。

Research Products

• [Journal Article] Histone H3K27 Demethylase Negatively Controls the Memory Formation of Antigen-Stimulated CD8+ T Cells (2019)
  • Author(s): Yamada Takeshi、Nabe Shogo、Toriyama Koji、Suzuki Junpei、Inoue Kazuki、Imai Yuuki、Shiraishi Atsushi、Takenaka Katsuto、Yasukawa Masaki、Yamashita Masakatsu
  • Journal Title: The Journal of Immunology Volume: 202 Issue: 4 Pages: 1088-1098
  • DOI: 10.4049/jimmunol.1801083
  • Peer Reviewed / Open Access
• [Journal Article] Reinforce the antitumor activity of CD8+ T cells via glutamine restriction (2018)
  • Author(s): Nabe Shogo、Yamada Takeshi、Suzuki Junpei、Toriyama Koji、Yasuoka Toshiaki、Kuwahara Makoto、Shiraishi Atsushi、Takenaka Katsuto、Yasukawa Masaki、Yamashita Masakatsu
  • Journal Title: Cancer Science Volume: 109 Issue: 12 Pages: 3737-3750
  • DOI: 10.1111/cas.13827
  • Peer Reviewed / Open Access
• [Journal Article] The tumor suppressor menin prevents effector CD8 T-cell dysfunction by targeting mTORC1-dependent metabolic activation (2018)
  • Author(s): Suzuki Junpei、Yamada Takeshi、Inoue Kazuki、Nabe Shogo、Kuwahara Makoto、Takemori Nobuaki、Takemori Ayako、Matsuda Seiji、Kanoh Makoto、Imai Yuuki、Yasukawa Masaki、Yamashita Masakatsu
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 1-12
  • DOI: 10.1038/s41467-018-05854-6
  • Peer Reviewed / Open Access
• [Presentation] Glutamine-dependent metabolic reprograming controls the signal transduction and differentiation od CD8 T cells. (2019)
  • Author(s): Toriyama K, Kuwahara M, Nomura S, Yamada T, Shiraishi A, and Yamashita M.
  • Organizer: 第48回日本免疫学会
• [Presentation] Utx negatively controls the memory formation of Ag-stimulated CD8+ T cells. (2019)
  • Author(s): Yamada T, Suzuki J, Arakawa Y, Toriyama K, Shiraishi A, Imai Y, Yasukawa M, and Yamashita M.
  • Organizer: 第48回日本免疫学会
• [Presentation] グルタミン代謝抑制によるCD8+ T細胞の抗腫瘍活性増強メカニズム (2018)
  • Author(s): 名部省吾、山田武司、鈴木淳平、安川正貴
  • Organizer: 第22回日本がん免疫学会
• [Presentation] T細胞のエネルギー代謝制御と免疫応答 (2018)
  • Author(s): 山田武司
  • Organizer: 第26回分子寄生虫フォーラム
  • Invited
• [Presentation] The tumor suppressor menin determines activated CD8 T cell fate by targeting mTORC1-dependent metabolic activation (2018)
  • Author(s): Suzuki J, Kuwahara M, Yamada T, Yasukawa M, and Yamashita M.
  • Organizer: The 47th Annual Meeting of the Japanese Society of Immunology
• [Presentation] 細胞内グルタミン代謝制御によるCD8+ T細胞の抗腫瘍活性増強効果 (2017)
  • Author(s): 名部彰悟, 山田武司, 鈴木淳平, 山下政克, 安川正貴
  • Organizer: 日本がん免疫学会
• [Presentation] Restricted glutamine metabolism enhances anti-tumor activity of CD8+ T cells (2017)
  • Author(s): Shogo Nabe, Takeshi Yamada, Junpei Suzuki, Masakatsu Yamashita, and Masaki Yasukawa
  • Organizer: 日本血液学会
• [Presentation] Histone H3K27 demethylase negatively controls memory formation of Ag-stimulated CD8+ T cells (2017)
  • Author(s): Takeshi Yamada, Koji Toriyama, Shogo Nabe, Makoto Kanoh, Yuuki Imai, Hiroaki Honda, and Masaki Yasukawa, Masakatsu Yamashita
  • Organizer: Kyoto T cell coference
  • Int'l Joint Research