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Regulatory mechanism of immune response through metabolic reprograming of T lymphocytes

Research Project

Project/Area Number 17H04086
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Immunology
Research InstitutionEhime University

Principal Investigator

Yamashita Masakatsu  愛媛大学, 医学系研究科, 教授 (00311605)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2017: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
KeywordsT細胞 / 代謝 / 免疫疾患 / 解糖系 / グルタミン代謝 / mTORC1 / Pgam1 / グルタミン / 感染免疫 / がん免疫 / 慢性炎症 / エピジェネティクス / α-ケトグルタル酸 / エピゲノム / 免疫記憶 / 抗腫瘍活性 / 疲弊 / 老化 / 代謝リプログラミング / ヒストン脱メチル化
Outline of Final Research Achievements

Although the important roles of metabolism in T cell activation and function have been demonstrated, the regulatory mechanism has not been fully elucidated. Furthermore, the influences of metabolic failure on the T cell-dependent immune response in vivo remain unclear. We therefore the role of glycolysis in the T cell-dependent immune response using T cell-specific Pgam1-deficient mice. Both CD8 and CD4 T cell-dependent immune responses were attenuated by Pgam1 deficiency. T cell-dependent inflammation was ameliorated in Pgam1-deficient mice. The development of regulatory T cells was not affected by the deletion of Pgam1 gene in vitro and in vivo. Glycolysis augments the activation of mTOR complex 1 (mTORC1) and the T-cell receptor (TCR) signals. Glutamine is required to augment glycolysis, increase mTORC1 activity and augment TCR signals. These findings suggest that mTORC1, glycolysis and glutamine affect each other and cooperate to induce T cell proliferation, differentiation.

Academic Significance and Societal Importance of the Research Achievements

今回の研究により、T細胞の機能、T細胞依存的な免疫応答は、代謝によって制御されていることが明らかとなった。さらに、T細胞代謝は、解糖系、グルタミン代謝、mTORC1シグナルが強調して働くことで制御されていることが示された。また、Th1、Th2やTh17細胞などのエフェクター細胞、エフェクター細胞と制御性T細胞、CD4 T細胞とCD8 T細胞など免疫細胞間、免疫応答の違いによって代謝経路が異なっていることが明らかとなった。今回の研究結果から、今後、代謝酵素が免疫疾患の新規治療シーズとなりうると考えられる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (21 results)

All 2019 2018 2017 Other

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (15 results) (of which Int'l Joint Research: 2 results,  Invited: 4 results) Remarks (3 results)

  • [Journal Article] Histone H3K27 Demethylase Negatively Controls the Memory Formation of Antigen-Stimulated CD8+ T Cells2019

    • 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

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Reinforce the antitumor activity of CD8+ T cells via glutamine restriction2018

    • 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

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The tumor suppressor menin prevents effector CD8 T-cell dysfunction by targeting mTORC1-dependent metabolic activation2018

    • 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

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] グルタミン代謝によるT細胞機能と炎症の制御2019

    • Author(s)
      桑原誠、野村俊介、鈴木淳平、山下政克
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 腫瘍抑制因子Meninはグルタミン代謝調節を介してCD8 T細胞老化をエピジェネティックに制御する2019

    • Author(s)
      鈴木淳平、山下政克
    • Organizer
      第42回日本分子生物学会大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] グルタミンとグルタミン代謝産物によるT細胞免疫応答の制御2019

    • Author(s)
      山下政克、鈴木淳平、桑原誠
    • Organizer
      第42回日本分子生物学会大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Long-lasting effect of glucocorticoids on immune response during CD8 T cell activation.2019

    • Author(s)
      Konishi Amane, Suzuki Junpei, Kuwahara Makoto, Matsumoto Akira, Yorozuya Toshihiro, Yamashita Masakatsu.
    • Organizer
      第48回日本免疫学会学術大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Glutamine regulates effector CD8 T cell differentiation through controlling glycolytic activity2019

    • Author(s)
      Toriyama Koji, Kuwahara Makoto, Nomura Shunsuke, Yamada Takeshi, Shiraishi Atsushi, Yamashita Masakatsu.
    • Organizer
      第48回日本免疫学会学術大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] The tumor suppressor menin inhibits CD8 T cell senescence by regulating autophagy.2019

    • Author(s)
      Suzuki Junpei, Konishi Amane, Yorozuya Toshihiro, Yamashita Masakatsu.
    • Organizer
      第48回日本免疫学会学術大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] The tumor suppressor menin prevents effector CD8 T cell dysfunction via metabolic restriction by targeting mTOR activation2018

    • Author(s)
      J. Suzuki, M. Kuwahara, M. Yamashita
    • Organizer
      Cell Symposia; Aging and Metabolism
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 腫瘍抑制因子Meninはグルタミン代謝調節を介してエピジェネティックにCD8 T細胞老化を制御する2018

    • Author(s)
      鈴木淳平、桑原誠、山田武司、安川正貴、山下政克
    • Organizer
      2018 抗加齢学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] α-ketoglutarate regulates CD8 T cell senescence via the prolongation of the central carbon metabolism activation2018

    • Author(s)
      SUZUKI Junpei, KUWAHARA Makoto, YAMADA Takeshi, YASUKAWA Masaki, YAMASHITA Masakatsu
    • Organizer
      2018 日本免疫学会総会・学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] The important role of glutaminase 1 (Gls1)-mediated glutamine metabolism in Th17 differentiation2018

    • Author(s)
      NOMURA Shunsuke, KUWAHARA Makoto, SAWASAKI Tatsuya, YAMASHITA Masakatsu
    • Organizer
      2018 日本免疫学会総会・学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] The transcriptional repressor Bach2 controls Th2-type immune response via interaction with Bach22017

    • Author(s)
      Makoto Kuwahara, Tatsuya Sawasaki, Masakatsu Yamashita
    • Organizer
      The 5th Annual Meeting of the International Cytokine and Interferon Society (ICIS 2017)
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] グルタミン代謝の抑制によるCD8+ T細胞の抗腫瘍活性の増強2017

    • Author(s)
      名部彰吾、山田武司,鈴木淳平,山下政克,安川正貴
    • Organizer
      第79回日本血液学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Meninはグルタミン代謝とヒストンH3K27脱メチル化調節を介してCD8 T細胞老化を制御する2017

    • Author(s)
      鈴木淳平,桑原誠,山田武司,安川正貴,山下政克
    • Organizer
      第79回日本血液学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] The critical role of Bach2 in regulating type2 inflammation2017

    • Author(s)
      Masakatsu Yamashita
    • Organizer
      The 46th Annual Meeting of The Japanese Society of Immunology
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] The transcriptional repressor Bach2 regulates differentiation of pathogenic Th2 cells2017

    • Author(s)
      Makoto Kuwahara, Masakatsu Yamashita
    • Organizer
      The 46th Annual Meeting of The Japanese Society of Immunology
    • Related Report
      2017 Annual Research Report
  • [Remarks] 愛媛大学大学院医学系研究科 免疫学・感染防御学

    • URL

      https://www.m.ehime-u.ac.jp/school/immunology/

    • Related Report
      2019 Annual Research Report
  • [Remarks] 愛媛大学大学院医学系研究科 免疫学・感染防御学講座

    • URL

      https://www.m.ehime-u.ac.jp/school/immunology

    • Related Report
      2018 Annual Research Report
  • [Remarks] 愛媛大学大学院医学系研究科免疫学・感染防御学講座

    • URL

      http://ehime-u-immunology.com

    • Related Report
      2017 Annual Research Report

URL: 

Published: 2017-04-28   Modified: 2021-02-19  

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