T細胞の自然免疫機能に立脚した新たな感染症治療戦略の創出

• Project/Area Number: 22K19418
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: Tohoku University
• Principal Investigator: 河部 剛史 東北大学, 医学系研究科, 准教授 (50834652)
• Co-Investigator(Kenkyū-buntansha): 石井 直人 東北大学, 医学系研究科, 教授 (60291267)
• Project Period (FY): 2022-06-30 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2023: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2022: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: T細胞 / 恒常性 / 感染免疫 / 自己免疫疾患 / CD4 T細胞 / 自然免疫

Outline of Research at the Start

現在、感染症治療の主体は抗菌薬や抗ウイルス薬などにより担われているが、これらの薬剤はそれぞれ標的微生物が限定的であるため、新興・再興感染症への対応は困難であった。一方、免疫機能を人為的に賦活化する「宿主志向型治療」が提唱されているが、炎症惹起による副作用が問題となっている。申請者は最近、獲得免疫の中核を担うはずのCD4 T細胞中に、自然免疫的感染防御機能を有する新規「MP細胞」を同定した。そこで本研究ではMP細胞の特性や感染防御機能、炎症惹起能の全容を解明することにより、副作用を最小化しつつあらゆる病原体に幅広く対応し得る新規「免疫賦活化治療」を創出することを目標とする。

Outline of Annual Research Achievements

これまで、病原体感染に対する治療法の主体は抗菌薬や抗ウイルス薬により担われてきた。これらの薬剤は感染症の発生件数の低減に多大な貢献を果たした一方、それぞれの薬剤により対象微生物が限定的であり、新興・再興感染症への迅速な対応は困難であった。それに対し、宿主の免疫機能を賦活化する「宿主志向型治療」が提唱されているが、過剰炎症などの副作用が問題となっている。
CD4 T細胞は獲得免疫応答に必須のリンパ球であるが、我々は同細胞中に、定常状態下において自己抗原認識依存的に産生され、病原体感染時には自然免疫的に機能する新規「MP細胞」を報告した。さらに、MP細胞がMP1、MP17などの複数のサブセットからなる可能性についても見出した。一方、MP細胞の持つ自己抗原反応性から、その過剰活性化により自己免疫疾患を発症する可能性も指摘されている。以上より、MP細胞の適切な人為的制御により、炎症副作用を最小化した新たな感染症治療戦略「免疫賦活化治療」を提起できるものと考えられる。そこで本研究では、MP細胞の質的特異性、自己免疫活性、感染防御機能を明らかにすることを目的とした。
研究の結果、MP細胞の鑑別マーカーとしてCD127、Sca1、Bcl2を同定し、また前者二者マーカーによってMP細胞自体が4群に分類されることを見出した（Front Immunol 2022）。また、これらMP 4分画のうち、CD127(hi) Sca1(hi)細胞がMP1に相当し自然免疫機能の主軸を担うこと、一方で同分画は免疫不全マウスにおいてIL-12依存的に腸炎を惹起しうる潜在性を有することが判明した。
以上より、マウスMP1サブセットの表現型や免疫学的機能が明らかになった。今後、同分画の存在をヒトにおいても検証することで、新規「免疫賦活化治療」（JMA J 2022）の創出につながるものと期待される。

Research Products

• [Journal Article] Memory-phenotype T細胞. (2023)
  • Author(s): 河部剛史
  • Journal Title: 臨床免疫・アレルギー科 (科学評論社) Volume: 80 Pages: 279-285
• [Journal Article] Homeostasis and immunological function of self-driven memory-phenotype CD4+ T lymphocytes (2023)
  • Author(s): Kawabe T
  • Journal Title: Immunol Med Volume: 46 Issue: 1 Pages: 1-8
  • DOI: 10.1080/25785826.2022.2129370
  • Peer Reviewed / Open Access
• [Journal Article] Memory-phenotype CD4⁺ T Lymphocytes: A Novel Therapeutic Target in Infectious or Autoimmune Diseases? (2022)
  • Author(s): Kawabe T
  • Journal Title: JMA Journal Volume: 5 Issue: 3 Pages: 298-306
  • DOI: 10.31662/jmaj.2022-0048
  • ISSN: 2433-328X, 2433-3298
  • Year and Date: 2022-07-15
  • Peer Reviewed / Open Access
• [Journal Article] IL-33-ILC2 axis promotes anti-tumor CD8+ T cell responses via OX40 signaling (2022)
  • Author(s): Okuyama Y, Okajima A, Sakamoto N, Hashimoto A, Tanabe R, Kawajiri A, Kawabe T, Ishii N
  • Journal Title: Biochem Biophys Res Commun Volume: 637 Pages: 9-16
  • DOI: 10.1016/j.bbrc.2022.11.006
  • Peer Reviewed
• [Journal Article] <i>Staphylococcus aureus</i> skin colonization promotes SLE-like autoimmune inflammation via neutrophil activation and the IL-23/IL-17 axis (2022)
  • Author(s): Terui Hitoshi、Yamasaki Kenshi、Wada-Irimada Moyuka、Onodera-Amagai Mayuko、Hatchome Naokazu、Mizuashi Masato、Yamashita Riu、Kawabe Takeshi、Ishii Naoto、Abe Takaaki、Asano Yoshihide、Aiba Setsuya
  • Journal Title: Science Immunology Volume: 7 Issue: 76
  • DOI: 10.1126/sciimmunol.abm9811
  • Peer Reviewed
• [Journal Article] Redefining the Foreign Antigen and Self-Driven Memory CD4+ T-Cell Compartments via Transcriptomic, Phenotypic, and Functional Analyses (2022)
  • Author(s): Kawabe T, Ciucci T, Kim KS, Tayama S, Kawajiri A, Suzuki T, Tanaka R, Ishii N, Jankovic D, Zhu J, Sprent J, Bosselut R, Sher A
  • Journal Title: Front Immunol Volume: 13 Pages: 870542-870542
  • DOI: 10.3389/fimmu.2022.870542
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differential regulation of transcription factor T-bet induction during NK cell development and T helper-1 cell differentiation (2022)
  • Author(s): Fang D, Cui K, Cao Y, Zheng M, Kawabe T, Hu G, Khillan JS, Li D, Zhong C, Jankovic D, Sher A, Zhao K, Zhu J
  • Journal Title: Immunity Volume: 55 Issue: 4 Pages: 639-655
  • DOI: 10.1016/j.immuni.2022.03.005
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Mitochondrial cysteinyl-tRNA synthetase (CARS2) -dependent sulfur metabolism exacerbates a mouse model of multiple sclerosis through antigen presentation. (2024)
  • Author(s): Hibiki Suzuki, Kyoga Hiraide, Yuya Kitamura, Shunichi Tayama, Kosuke Sato, Keita Koinuma, Yuko Okuyama, Takeshi Kawabe, Takaaki Akaike, Naoto Ishii.
  • Organizer: 第52回日本免疫学会学術集会
• [Presentation] Memory-phenotype CD4+ T lymphocytes can contribute to tumor control without inducing graft-versus-host disease. (2024)
  • Author(s): Ziying Yang, Jing Li, Hideaki Watanabe, Keita Koinuma, Akihisa Kawajiri, Kosuke Sato, Shunichi Tayama, Yuko Okuyama, Naoto Ishii, Takeshi Kawabe.
  • Organizer: 第52回日本免疫学会学術集会
• [Presentation] Reactive persulfide controls intestinal inflammation by suppressing CD4+ T cell proliferation. (2024)
  • Author(s): Shunichi Tayama, Yuya Kitamura, Kyoga Hiraide, Hibiki Suzuki, Jing Li, Ziying Yang, Kosuke Sato, Akihisa Kawajiri, Yuko Okuyama, Takeshi Kawabe, Takaaki Akaike, Naoto Ishii.
  • Organizer: 第52回日本免疫学会学術集会
• [Presentation] Regulatory T cells tonically inhibit spontaneous activation of naturally arising memory-phenotype CD4+ T lymphocytes. (2024)
  • Author(s): Jing Li, Ziying Yang, Akihisa Kawajiri, Kosuke Sato, Shunichi Tayama, Naoto Ishii, Takeshi Kawabe.
  • Organizer: 第52回日本免疫学会学術集会
• [Presentation] Memory-phenotype CD4+ T lymphocytes rapidly accumulate in ischemic organs and exacerbate tissue injury in an innate manner. (2024)
  • Author(s): Kosuke Sato, Akihisa Kawajiri, Jing Li, Ziying Yang, Shunichi Tayama, Kenshiro Matsuda, Chigusa Oda, Akira Shibuya, Motoshi Wada, Naoto Ishii, Takeshi Kawabe.
  • Organizer: 第52回日本免疫学会学術集会
• [Presentation] Redefining immunological significance of T cell self-reactivity. (2023)
  • Author(s): Takeshi Kawabe
  • Organizer: 第10回T cell seminar
  • Invited
• [Presentation] Self-driven memory-phenotype cells: a naturally arising CD4+ T lymphocyte population possessing innate immune function. (2023)
  • Author(s): Takeshi Kawabe
  • Organizer: The RIKEN IMS-JSI International Symposium on Immunology 2023
  • Int'l Joint Research / Invited
• [Presentation] CD127 and Sca1 mark self-driven memory-phenotype CD4+ T cells that differ from foreign antigen-specific memory cells and possess inflammatogenic and anti-tumor activities. (2023)
  • Author(s): Takeshi Kawabe, Thomas Ciucci, Kwang Soon Kim, Ziying Yang, Akihisa Kawajiri, Shunichi Tayama, Naoto Ishii, Dragana Jankovic, Jinfang Zhu, Jonathan Sprent, Remy Bosselut, Alan Sher.
  • Organizer: Immunology 2023, Annual Meeting of the American Association of Immunologists
  • Int'l Joint Research
• [Presentation] Self antigen-driven, undifferentiated memory-phenotype CD4+ T lymphocytes can induce mild and systemic inflammation by differentiating into effector and regulatory T cells. (2023)
  • Author(s): Akihisa Kawajiri, Jing Li, Ziying Yang, Keita Koinuma, Hye Jin Yoon, Minami Ishii, Shunichi Tayama, Kosuke Sato, Yuko Okuyama, Hideo Harigae, Naoto Ishii, Kazuyoshi Ishigaki, Jinfang Zhu, Kwang Soon Kim, Takeshi Kawabe.
  • Organizer: Immunology 2023, Annual Meeting of the American Association of Immunologists
  • Int'l Joint Research
• [Presentation] Reactive persulfide controls intestinal inflammation by suppressing CD4+ T cell proliferation. (2023)
  • Author(s): Shunichi Tayama, Yuya Kitamura, Kyoga Hiraide, Jing Li, Ziying Yang, Akihisa Kawajiri, Kosuke Sato, Yuko Okuyama, Takeshi Kawabe, Takaaki Akaike, Naoto Ishii.
  • Organizer: Immunology 2023, Annual Meeting of the American Association of Immunologists
  • Int'l Joint Research
• [Presentation] ILC2-derived OX40L-OX40 signal promotes cytotoxic CD8+ T cell-mediated antitumor immunity in murine melanoma. (2022)
  • Author(s): Yuko Okuyama, Akira Okajima, Nao Sakamoto, Ryuto Tanabe, Ayaka Hashimoto, Atsuko Asao, Ziying Yang, Akihisa Kawajiri, Takeshi Kawabe, Naoto Ishii
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] Immunological Functions of Memory-Phenotype CD4+ T lymphocytes in Anti-Tumor Responses and Graft-versus-Host Disease. (2022)
  • Author(s): Ziying Yang, Hideaki Watanabe, Jing Li, Akihisa Kawajiri, Kosuke Sato, Shunichi Tayama, Yuko Okuyama, Naoto Ishii, Takeshi Kawabe
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] Rapid accumulation of circulating memory-phenotype CD4+ T lymphocytes in the gut critically contributes to tissue injury driven by intestinal ischemia and reperfusion. (2022)
  • Author(s): Kosuke Sato, Jing Li, Ziying Yang, Akihisa Kawajiri, Shunichi Tayama, Yuko Okuyama, Motoshi Wada, Naoto Ishii, Takeshi Kawabe
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] Phenotypic and functional analyses reveal self-driven memory-phenotype CD4+ T lymphocytes as a heterogeneous population distinct from foreign antigen-specific memory cells. (2022)
  • Author(s): Takeshi Kawabe, Thomas Ciucci, Kwang Soon Kim, Shunichi Tayama, Akihisa Kawajiri, Naoto Ishii, Dragana Jankovic, Jinfang Zhu, Jonathan Sprent, Remy Bosselut, Alan Sher
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] Mitochondrial cysteinyl-tRNA synthetase (CARS2)-dependent sulfur metabolism exacerbates experimental autoimmune encephalomyelitis in mice. (2022)
  • Author(s): Kyoga Hiraide, Yuya Kitamura, Shunichi Tayama, Yuko Okuyama, Kosuke Sato, Hibiki Suzuki, Keita Koinuma, Takeshi Kawabe, Naoto Ishii
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] Self-reactive memory-phenotype CD4+ T lymphocytes can induce mild and systemic inflammation by differentiating into effector and regulatory T cells. (2022)
  • Author(s): Akihisa Kawajiri, Jing Li, Ziying Yang, Keita Koinuma, Kosuke Sato, Shunichi Tayama, Yuko Okuyama, Hideo Harigae, Naoto Ishii, Jinfang Zhu, Kwang Soon Kim, Takeshi Kawabe
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] CARS2-dependent sulfur metabolism controls intestinal inflammation by suppressing CD4+ T cell proliferation. (2022)
  • Author(s): Shunichi Tayama, Takeshi Kawabe, Kyoga Hiraide, Jing Li, Ziying Yang, Kosuke Sato, Akihisa Kawajiri, Yuko Okuyama, Naoto Ishii
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] Excess proliferation and activation of self-reactive memory-phenotype CD4+ T lymphocytes are tonically inhibited by regulatory T cells in steady state. (2022)
  • Author(s): Jing Li, Ziying Yang, Akihisa Kawajiri, Kosuke Sato, Shunichi Tayama, Yuko Okuyama, Naoto Ishii, Takeshi Kawabe
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] 自己抗原反応性Memory-phenotype CD4+T細胞の炎症惹起能 (2022)
  • Author(s): 川尻昭寿, 李静, 楊子嬰, 鯉沼佳太, 佐藤皓祐, 田山舜一, 奥山祐子, 張替秀郎, 石井直人, 河部剛史
  • Organizer: 第74回日本細菌学会東北支部会学術集会
• [Presentation] Memory-phenotype cells: naturally arising CD4+ T lymphocytes possessing innate immune function (2022)
  • Author(s): Takeshi Kawabe
  • Organizer: Symposium in honor of Dr. Alan Sher and IBS/LPD scientific achievements - Critical cooperation at the interface between infection and immunity
  • Int'l Joint Research / Invited