Investigation of the molecular mechanisms to control T-cell exhaustion

• Project/Area Number: 26460579
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Ehime University
• Principal Investigator: Yamada Takeshi 愛媛大学, 医学系研究科, 准教授 (40333554)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: T細胞疲弊 / CD8 / 慢性型感染症 / Menin / エフェクター維持 / エネルギー代謝 / CD8陽性T細胞 / T細胞の疲弊 / T細胞 / 細胞疲弊

Outline of Final Research Achievements

It has been known that T-cell exhaustion reduces function of T cells to eliminate pathogens during chronic infections such as HIV infection. In this study, we thus analyzed the inducible mechanisms of T-cell exhaustion using a mouse model. Our study revealed that T-cell exhaustion was induced in antigen-specific CD8 T cells lacking a tumor suppressor Menin after infection with an intracellular pathogen Listeria. We observed that Menin deficiency enhanced terminal-effector differentiation and increased expression of inhibitory receptors in activated CD8 T cells, suggesting that Menin controls differentiation into effectors and inhibits T-cell exhaustion.

Research Products

• [Journal Article] Menin Plays a Critical Role in the Regulation of the Antigen-Specific CD8+ T Cell Response upon Listeria Infection (2016)
  • Author(s): Yamada T, Kanoh M, Nabe S, Yasuoka T, Suzuki J, Matsumoto A, Kuwahara M, Maruyama S, Fujimoto T, Sakisuka R, Yasukawa M, and Yamashita M.
  • Journal Title: Journal of Immunology Volume: 197 Issue: 10 Pages: 4079-4089
  • DOI: 10.4049/jimmunol.1502295
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The transcriptional repressor Gfi1 plays a critical role in the development of NKT1- and NKT2-type iNKT cells (2016)
  • Author(s): Yasuoka, T. Yasukawa M, et al.
  • Journal Title: PLoS One Volume: 11 Issue: 6 Pages: e0157395-e0157395
  • DOI: 10.1371/journal.pone.0157395
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Menin-Bach2 axis is critical for regulating CD4 T cell senescence and cytokine homeostasis (2014)
  • Author(s): Kuwahara, M., Suzuki, J., Tofukuji, S., Yamada, T., Kanoh, M., Matsumoto, A., Maruyama, S., Kometani, K., Kurosaki, T., Ohara, O., Nakayama, T., Yamashita, M
  • Journal Title: Nature Comm Volume: 5 Issue: 1 Pages: 3555-3555
  • DOI: 10.1038/ncomms4555
  • Peer Reviewed / Open Access
• [Presentation] Histone H3K27 demethylase negatively controls memory formation of Ag-stimulated CD8+ T cells. (2017)
  • Author(s): Yamada Takeshi
  • Organizer: 7th International Workshop Kyoto T cell conference
  • Place of Presentation: 京都大学芝蘭会館
  • Year and Date: 2017-03-13
  • Int'l Joint Research
• [Presentation] CD8 陽性T細胞の感染免疫応答における腫瘍抑制因子Meninの役割 (2016)
  • Author(s): 藤本拓也
  • Organizer: 日本感染症学会
  • Place of Presentation: 仙台国際センター、宮城県仙台市
  • Year and Date: 2016-04-15
• [Presentation] Menin plays a critical role in the survival of antigen-specific activated CD8+ T cells (2015)
  • Author(s): 山田武司
  • Organizer: 日本免疫学会
  • Place of Presentation: 札幌コンベンションセンター、北海道札幌市
  • Year and Date: 2015-11-18
• [Presentation] Menin plays a critical role in the expansion and maintenance of antigen-specific CD8+ T cells upon infection. (2014)
  • Author(s): 山田武司
  • Organizer: 日本免疫学会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Crutial role of Menin in the epigenetic regulation of Satb1 expression in CD8 T cells. (2014)
  • Author(s): 鈴木淳平
  • Organizer: 日本免疫学会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-12-10 – 2014-12-12