Integrated regulation of T cell signaling and differentiation by glutamine

• Project/Area Number: 20H03504
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Ehime University
• Principal Investigator: Yamashita Masakatsu 愛媛大学, 医学系研究科, 教授 (00311605)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2022: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2020: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
• Keywords: T細胞 / グルタミン / シグナル伝達 / 解糖系 / ヒストンH3K27 / 脱メチル化 / 代謝 / エピジェネティクス / 免疫疾患 / Jak阻害剤 / リソソーム / オートファジー / 免疫 / Pgam1

Outline of Research at the Start

T細胞における、シグナル伝達研究と増殖・分化研究の間には大きなギャップが存在している。申請者らは、そのギャップを埋める細胞応答が、抗原認識に伴って誘導される代謝リプログラミングであると考えている。本申請では、（1）グルタミンによる代謝リプログラミング制御機構、（2）代謝リプログラミングを介したT細胞シグナル伝達調節機構、(3）代謝リプログラミングを介したT細胞分化制御機構を明らかにし、最終的には、(4)代謝調節による新規免疫制御の方法論の確立を目指す。

Outline of Final Research Achievements

The increased activity of the glycolytic system upon T cell antigen recognition is required for activation of glutamine metabolism, and glutamine maintains activation of the glycolytic system via sustained activity of mTOR. In other words, it was suggested that the glycolytic system and glutamine metabolism may form a feed-forward loop to prolong signals via TCR and cytokine receptors and maintain T cell activation. These results indicate that glycolytic activation in T cells upon antigen recognition is essential for the induction of normal T cell-dependent immune responses and is a therapeutic target for the treatment of immunological diseases. We also found that glutamine may regulate T cellular senescence via modulation of autophagy.

Academic Significance and Societal Importance of the Research Achievements

グルタミンが活性化T細胞における解糖系、シグナル伝達の維持に必要であることが明らかにするとともに、活性化T細胞におけるグルタミン（代謝）がオートファジーの調節を介してT細胞老化を制御している可能性を新たに見出したことが、今回の研究成果の学樹的意義である。また、グルタミン流入阻害やT細胞解糖系酵素阻害が免疫疾患の治療標的になることを示したことは、免疫抑制による疾患治療の新しい選択肢を提示したという点において社会的なインパクトは大きい。

Research Products

• [Journal Article] The histone demethylase Utx controls <scp>CD8</scp> ⁺ T‐cell‐dependent antitumor immunity via epigenetic regulation of the effector function (2023)
  • Author(s): Noda Haruna、Suzuki Junpei、Matsuoka Yuko、Matsumoto Akira、Kuwahara Makoto、Kamei Yoshiaki、Takada Yasutsugu、Yamashita Masakatsu
  • Journal Title: Cancer Science Volume: - Issue: 7 Pages: 2787-2797
  • DOI: 10.1111/cas.15814
  • Peer Reviewed / Open Access
• [Journal Article] The Inhibition of Glycolysis in T Cells by a Jak Inhibitor Ameliorates the Pathogenesis of Allergic Contact Dermatitis in Mice (2023)
  • Author(s): Okamoto Michiko、Omori-Miyake Miyuki、Kuwahara Makoto、Okabe Masataka、Eguchi Mariko、Yamashita Masakatsu
  • Journal Title: Journal of Investigative Dermatology Volume: - Issue: 10 Pages: 1973-1982.e5
  • DOI: 10.1016/j.jid.2023.03.1667
  • Peer Reviewed / Open Access
• [Journal Article] Senescent <scp>CD8</scp> ⁺ T cells acquire <scp>NK</scp> cell‐like innate functions to promote antitumor immunity (2023)
  • Author(s): Kakuda Toshio、Suzuki Junpei、Matsuoka Yuko、Kikugawa Tadahiko、Saika Takashi、Yamashita Masakatsu
  • Journal Title: Cancer Science Volume: x Issue: 7 Pages: 2810-2820
  • DOI: 10.1111/cas.15824
  • Peer Reviewed / Open Access
• [Journal Article] Glucocorticoid imprints a low glucose metabolism onto CD8 T cells and induces the persistent suppression of the immune response (2022)
  • Author(s): Konishi Amane、Suzuki Junpei、Kuwahara Makoto、Matsumoto Akira、Nomura Shunsuke、Soga Tomoyoshi、Yorozuya Toshihiro、Yamashita Masakatsu
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 588 Pages: 34-40
  • DOI: 10.1016/j.bbrc.2021.12.050
  • Peer Reviewed / Open Access
• [Journal Article] Insomnia and depressive behavior of MyD88-deficient mice: Relationships with altered microglial functions (2022)
  • Author(s): Mohammed E. Choudhury, Kanta Mikami, Yuiko Nakanishi, Taisei Matsuura, Ryo Utsunomiya, Hajime Yano, Madoka Kubo, Rina Ando, Jun Iwanami, Masakatsu Yamashita, Masahiro Nagai, JunyaTanaka
  • Journal Title: Journal of Neuroimmunology Volume: 363 Pages: 577794-577794
  • DOI: 10.1016/j.jneuroim.2021.577794
  • Peer Reviewed
• [Journal Article] The Loss of H3K27 Histone Demethylase Utx in T Cells Aggravates Allergic Contact Dermatitis (2021)
  • Author(s): Inoue Takashi、Omori-Miyake Miyuki、Maruyama Saho、Okabe Masataka、Kuwahara Makoto、Honda Hiroaki、Miura Hiromasa、Yamashita Masakatsu
  • Journal Title: The Journal of Immunology Volume: 207 Issue: 9 Pages: 2223-2234
  • DOI: 10.4049/jimmunol.2001160
  • Peer Reviewed / Open Access
• [Journal Article] T cell-specific deletion of Pgam1 reveals a critical role for glycolysis in T cell responses. (2020)
  • Author(s): Toriyama K, Kuwahara M, Kondoh H, Mikawa T, Takemori N, Konishi A., Yorozuya T, Yamada T, Soga T., Shiraishi A, and Yamashita M.
  • Journal Title: Communications Biology Volume: 3 Issue: 1 Pages: 1-13
  • DOI: 10.1038/s42003-020-01122-w
  • Peer Reviewed / Open Access
• [Journal Article] Glycolysis and subsequent mevalonate biosynthesis play an important role in Th2 cell differentiation. (2020)
  • Author(s): Yagi Y, Kuwahara M, Suzuki J, Imai Y and Yamashita M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 530 Issue: 2 Pages: 355-361
  • DOI: 10.1016/j.bbrc.2020.08.009
  • Peer Reviewed / Open Access
• [Presentation] T細胞における解糖経路の阻害はアレルギー性接触皮膚炎の病態を改善する (2022)
  • Author(s): 岡本典子、ミヤケ深雪、桑原誠、江口真理子、山下政克
  • Organizer: 日本アレルギー学会学術大会
• [Presentation] T細胞自然免疫応答の代謝-エピゲノム調節とアレルギー性気道炎症慢性化への関与 (2022)
  • Author(s): 桑原誠、松岡祐子、鈴木淳平、山下政克
  • Organizer: 日本生化学会
  • Invited
• [Presentation] Tumor suppressor Menin, a regulator of T cell senescence (2022)
  • Author(s): Masakatsu Yamashita
  • Organizer: 23rd Northern Asian Symposium 2022
  • Int'l Joint Research / Invited
• [Presentation] Utx, a histone demethylase, promotes anti-tumor response of CD8 T cells over epigenetic regulation of Cxcr3 expression (2022)
  • Author(s): Haruna Noda、Junpei Suzuki、Kana Taguchi、Kanako Nishiyama、Akari Murakami、Yoshiaki Kamei 、Masakatsu Yamashita
  • Organizer: 第81回日本がん学会学術総会
• [Presentation] グルタミンによるCD8 T細胞がん免疫応答の制御 (2022)
  • Author(s): 山下政克
  • Organizer: 第8回がんと代謝研究会
  • Invited
• [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/
• [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/
• [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/