Investigations of the role of glutamine metabolism in the T cell fate determination

• Project/Area Number: 16K19158
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Immunology
• Research Institution: Ehime University
• Principal Investigator: Kuwahara Makoto 愛媛大学, 医学部附属病院, 助教(病院教員) (00568214)
• Research Collaborator: YAMASHITA Masakatsu
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: T細胞運命決定 / グルタミン代謝 / Th2 / Utx / T 細胞老化 / a-ケトグルタル酸 / H3K27me2/3 / 活性化 T 細胞運命決定 / 獲得免疫

Outline of Final Research Achievements

We assessed the role of glutamine metabolism in the fate determination of activated T cells in this study. The deprivation of glutamine from culture medium or the pharmacological inhibition of glutamine metabolism suppressed Th2 differentiation and the induction of T cell senescent phenotype in vitro. The administration of alpha-ketoglutarate (α-KG) in cultures under glutamine-deprived conditions restored Th2 differentiation and induced T cell senescent phenotype indicating thatα-KG derived from glutamine is required for Th2 differentiation and induction of T cell senescent phenotype. Furthermore, we found that α-KG-dependent demethylation of the Th2 cytokine gene loci by the H3K27 demethylase Utx is required for the efficient Th2 differentiation. Alpha-KG-dependent histone H3K27 demethylation is also involved in the induction of senescence. These findings reveal the novel role of glutamine metabolism in regulating Th2 differentiation and induction of T cell senescent phenotype.

Research Products

• [Journal Article] The critical role of Bach2 in regulating type-2 chronic airway inflammation (2018)
  • Author(s): Yamashita Masakatsu、Kuwahara Makoto
  • Journal Title: International Immunology Volume: - Issue: 9 Pages: 397-402
  • DOI: 10.1093/intimm/dxy020
  • Peer Reviewed / Open Access
• [Journal Article] Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis. (2017)
  • Author(s): Ebina-Shibuya R, Matsumoto M, Kuwahara M, Jang KJ, Sugai M, Ito Y, Funayama R, Nakayama K, Sato Y, Ishii N, Okamura Y, Kinoshita K, Kometani K, Kurosaki T, Muto A, Ichinose M, Yamashita M, Igarashi K.
  • Journal Title: The Journal of biological chemistry Volume: 292 Issue: 44 Pages: 18098-18112
  • DOI: 10.1074/jbc.m117.808535
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bach2-Batf interactions control Th2-type immune response by regulating the IL-4 amplification loop. (2016)
  • Author(s): Kuwahara M, Ise W, Ochi M, Suzuki J, Kometani K, Maruyama S, Izumoto M, Matsumoto A, Takemori N, Takemori A, Shinoda K, Nakayama T, Ohara O, Yasukawa M, Sawasaki T, Kurosaki T, Yamashita M.
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 12596-12596
  • DOI: 10.1038/ncomms12596
  • Peer Reviewed / Open Access
• [Presentation] The transcriptional repressor Bach2 regulates differentiation of pathogenic Th2 cells. (2017)
  • Author(s): Kuwahara Makoto, Yamashita Masakatsu
  • Organizer: 第 46 回日本免疫学会総会・学術集会
• [Presentation] The transcriptional repressor Bach2 controls Th2-type immune response via interaction with Batf. (2017)
  • Author(s): Kuwahara Makoto, Sawasaki Tatsuya, Yamashita Masakatsu
  • Organizer: The 5th Annual Meeting of the International Cytokine and Interferon Society
  • Int'l Joint Research
• [Presentation] Bach2-Batf interactions control Th2-type airway chronic inflammation. (2017)
  • Author(s): Kuwahara Makoto, Yamashita Masakatsu
  • Organizer: The 19th Takeda Science Foundation Symposium on Bioscience Chronic Inflammation -Initiation, Progression and Regulation-
• [Presentation] TCR-mediated activation of glutamine metabolism play a critical role in regulating Th2 cell differentiation (2016)
  • Author(s): Makoto Kuwahara, Kazuki Inoue, Yuuki Imai, Masakatsu Yamashita
  • Organizer: 第 65 回日本アレルギー学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2016-06-18
• [Presentation] 腫瘍抑制因子 Menin による T 細胞老化制御 (2016)
  • Author(s): 桑原 誠、鈴木 淳平、山田武司、山下 政克
  • Organizer: 第 16 回日本抗加齢医学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-06-11
  • Invited
• [Remarks] 愛媛大学大学院医学系研究科免疫学・感染防御学（研究テーマ）
  • URL: http://ehime-u-immunology.com/index.html