Role of T cell on lung homeostasis and dieseases

• Project/Area Number: 21K08205
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Ehime University
• Principal Investigator: Kuwahara Makoto 愛媛大学, 医学系研究科, 講師 (00568214)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: T細胞自然免疫応答 / Bach2 / IL-7R / IL-33R / アレルギー性気道炎症 / 肺胞蛋白症 / IL-33R+ Th2 / T細胞 / 気道炎症

Outline of Research at the Start

転写因子Bach2の一塩基多型は様々な臓器特異的免疫疾患と関連することが報告されている。申請者はT細胞特異的Bach2欠損マウスの肺で、IL-33受容体陽性(IL-33R+)Th2細胞が増加し、アレルギー性気道炎症が自然発症すること、T細胞特異的Bach2トランスジェニックマウスの肺で、Tregが増加して肺胞蛋白症が自然発症することを見出した。そこで本研究では、T細胞のBach2の発現異常がT細胞の機能不全と、それに伴う呼吸器疾患を引き起こすことを明らかにする。最終的には、T細胞のBach2の適切な発現調節が肺の恒常性に重要であり、その破綻が呼吸器疾患誘発するという新規概念の提唱を目指す。

Outline of Final Research Achievements

A reduction in Bach2 expression in lung CD4 T cells was found to activate IL-7-mTOR signalling in Th2 cells, leading to the differentiation of IL-33R+ Th2 cells. These IL-33R+ Th2 cells then prolonged Th2 innate immune responses in the lung environment in an IL-7/IL-33-dependent manner, ultimately leading to the development of chronic allergic airway inflammation. Interestingly, the absence of reduced Bach2 expression in Treg and CD8 T cells in the lungs led to the formation of an alveolar proteinosis-like pathology. These findings highlight the complex interplay between Bach2 expression and the maintenance of lung homeostasis.

Academic Significance and Societal Importance of the Research Achievements

T 細胞における Bach2 の発現不全が 不適切な免疫応答を誘導し、それにより肺の恒常性が破綻することで様々な呼吸器疾患が発症するという新規概念の提唱を目指す本申請研究は、学術的な独自性が極めて高い。また、本研究の進展によって得られた成果により、呼吸器疾患発症の新規メカニズムを提唱できるだけでなく、Bach2 下流分子を標的とした新規治療法の開発研究に発展する可能性が高い。つまり本申請研究は、「T 細胞による肺恒常性維持という新規概念の提唱」、「呼吸器疾患の発症機構の統合的理解」、「呼吸器疾患の新規治療戦略の提唱」という３つの側面を持つ創造性の高い研究である。

Research Products

• [Journal Article] The early neutrophil-committed progenitors aberrantly differentiate into immunoregulatory monocytes during emergency myelopoiesis (2023)
  • Author(s): Ikeda N, Kubota H, Suzuki R, Morita M, Yoshimura A, Osada Y, Kishida K, Kitamura D, Iwata A, Yotsumoto S, Kurotaki D, Nishimura K, Nishiyama A, Tamura T, Kamatani T, Tsunoda T, Murakawa M, Asahina Y, Hayashi Y, Harada H, Harada Y, Yokota A, Hirai H, Seki T, Kuwahara M, Yamashita M, Shichino S, Tanaka M, Asano K.
  • Journal Title: Cell Reports Volume: 42 Issue: 3 Pages: 112165-112165
  • DOI: 10.1016/j.celrep.2023.112165
  • 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): Michiko Okamoto, Miyuki Omori-Miyake, Makoto Kuwahara, Masataka Okabe, Mariko Eguchi, Masakatsu Yamashita
  • Journal Title: Journal of Investigative Dermatology Volume: － Issue: 10 Pages: 1973-1982.e5
  • DOI: 10.1016/j.jid.2023.03.1667
  • Peer Reviewed
• [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] 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] 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
• [Presentation] Bach2 controls IL-33-dependent innate Th2 cell response through regulation of Jmjd3 (Kdm6b), a histoneH3K27me2/3 demethylase (2023)
  • Author(s): Makoto Kuwahara, Junpei Suzuki, Akira Matsumoto, Yukihiro Nakamura, Hiroaki Honda, Naohiko Hamaguchi, Osamu Yamaguchi, Masakatsu Yamashita
  • Organizer: 第72回日本アレルギー学会学術大
• [Presentation] A thioamide-related small compound SH-2251, an inhibitor of transcriptional repressor Gfi1 expression, inhibits IL-7/IL-33-dependent innate Th2 response and Th2-type chronic lung inflammation (2022)
  • Author(s): Kuwahara Makoto, Suzuki Junpei, Maruyama Saho, Nakamura Yukihiro, Hamaguchi Naohiko, Yamaguchi Osamu, Yamashita Masakatsu
  • Organizer: 第71回日本アレルギー学会学術大
• [Presentation] Transcriptional repressor Gfi1 induces IL-7/IL-33-dependent innate-like Th2 responses by activating cellular metabolism (2021)
  • Author(s): 桑原 誠、山下 政克
  • Organizer: 第70回日本アレルギー学会
• [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] 愛媛大学免疫学感染防御学
  • URL: https://www.m.ehime-u.ac.jp/school/immunology/