• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Revealing immune cell network formed by novel self-reactive T lymphocytes

Research Project

Project/Area Number 20KK0362
Research Category

Fund for the Promotion of Joint International Research (Fostering Joint International Research (A))

Allocation TypeMulti-year Fund
Review Section Basic Section 49070:Immunology-related
Research InstitutionTohoku University

Principal Investigator

河部 剛史  東北大学, 医学系研究科, 准教授 (50834652)

Project Period (FY) 2021 – 2024
Project Status Granted (Fiscal Year 2023)
Budget Amount *help
¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000)
KeywordsT細胞 / 恒常性 / 制御性T細胞 / CD4 T細胞 / 免疫記憶 / 感染免疫 / 自己免疫疾患 / イメージング
Outline of Research at the Start

CD4 T細胞は外来抗原特異的獲得免疫反応に必須のリンパ球である。これに対し申請者は、自己抗原特異的に産生され恒常的に準活性化状態を呈する「MP細胞」を同定し、その極めて特徴的な自然免疫機能を発見した(Sci Immunol 2017)。本研究は、同細胞の質的特異性や分化・活性化機構を詳らかにするとともに、MP細胞と古典的抗原特異的メモリー細胞との差異やMP-DC-Treg間相互連関を解明し、MP細胞を取りまく免疫細胞ネットワークの全容解明を図るものである。

Outline of Annual Research Achievements

CD4 T細胞は外来抗原に対する獲得免疫応答に必須の役割を果たすリンパ球である。すなわち病原体感染時、外来抗原特異的TCRを有するナイーブT細胞は活性化しエフェクターさらにはメモリー細胞へと分化し、病原体を生体内から排除する。これらの「古典的」T細胞集団に加え、我々は、CD4 T細胞中に、ナイーブ細胞が自己抗原を認識することにより恒常的に産生され、感染時には自然免疫的な様式で生体防御に寄与する「Memory-phenotype cell(MP細胞)」を報告した(Sci Immunol 2017, Nat Commun 2020)。そこで本研究では、世界最大の研究施設である米国NIHとの共同研究により、MP細胞の鑑別マーカー、質的特異性、分化・活性化機構、免疫学的機能を明らかにし、さらには同細胞を取り巻く免疫細胞ネットワークの全容を究明することを目的とした。
昨年度までの研究の結果、我々は、MP細胞鑑別マーカーとしてIL-7Ra、Sca1、Bcl2を同定していた(Front Immunol 2022)。これらのマーカーを用い、MP細胞自身も複数のサブセット(IL-7Ra(lo) Bcl2(lo), IL-7Ra(hi) Bcl2(lo), IL-7Ra(hi) Bcl2(hi))に分類されることが分かったため、本年度はこれらMP細分画の産生・維持・分化・活性化機構や免疫学的機能などを解析した。また、MP細胞のもつ潜在的炎症惹起能は定常状態下においてはTreg、DCにより厳密に制御されていることも判明しつつある。
次年度も今年度の研究を継続し、MP細胞と「古典的」メモリー細胞との質的差異、MP細胞のheterogeneityと恒常的分化機構、自己免疫疾患惹起能などの究明にむけて、NIHとの国際共同研究のさらなる発展を図る予定である。

Current Status of Research Progress
Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

(I, IV) MP細胞の質的特異性・鑑別マーカーの解明:昨年度までの研究の結果、自己抗原反応性MP細胞と外来抗原特異的メモリー細胞とを区分するマーカーとしてIL-7Ra、Sca1、Bcl2を同定した(Front Immunol 2022)。即ち、MP細胞におけるこれらのマーカー発現はメモリー細胞におけるそれと比較して総じて低い。本知見は、IL-7 - Bcl2シグナルの強弱がMP・メモリー細胞の本質的な差異を規定する可能性を示唆するものであり、現在、Bcl2-transgenicマウスやCD4CreERT2 x Bcl2(flox)マウスを用いて本仮説を検証中である。また、本マーカーを用い、MP細胞自体がいくつかの亜集団(IL-7Ra(lo) Bcl2(lo), IL-7Ra(hi) Bcl2(lo), IL-7Ra(hi) Bcl2(hi))に分類され得ることが明らかになった。本年度はこれらのMP亜集団のさらなる表現型解析や機能解析、TCR配列解析等も行った。
(II) MP細胞の分化・活性化機構の究明:上述のMP亜集団のうち、IL-7Ra(hi) Bcl2(hi) MP細胞に多くのMP1/17細胞が含まれることが判明した。また、特定の分化傾向を呈さない「MP0」細胞の存在についても示唆された。現在、それぞれのMP亜集団を定常状態あるいは免疫不全マウスに移入するなどの手法により、それぞれのMP亜集団の定常的分化機構や自然免疫機能を解析中である。
(III, V) MP細胞による自己免疫疾患発症機構の推究、MP細胞 - 周辺細胞間の相互連関の解明:MP細胞がRag2 KOマウスやFoxp3-DTRマウス体内でIL-12/23依存的にMP1/17へと分化し全身炎症を惹起しうる可能性を見出した。現在、MP細胞の分化・活性化におけるDC、Treg等の役割を解明中である。

Strategy for Future Research Activity

(I, IV) MP細胞の質的特異性の解明、MP細胞を特定しうるマーカーの同定:IL-7Ra、Bcl2により定義されるMP 3分画のさらなる解析を通じ、これらのサブセットとMP0, MP1, MP17などとの関係性を解明するとともに、MP0の特性(TCR配列、特異的細胞表面マーカー、転写因子など)を明らかにする。
(II) MP細胞の分化・活性化機構の究明:MP0, MP1, MP17を定常状態マウスやリンパ球減少状態マウスに移入するなどにより、これらの細胞分画の分化能、安定性、可塑性を明らかにするとともにその分子メカニズムを探求する。
(III, V) MP細胞による自己免疫疾患発症機構の推究、MP細胞-周辺細胞間の相互連関の解明:Rag2 KOマウスやFoxp3-DTRマウス体内におけるMP0, MP1, MP17の挙動を引き続き解析することで、MP細胞ホメオスタシスにおけるMP、Treg、DCの三者間相互作用の役割を究明する予定である。

Report

(3 results)
  • 2023 Research-status Report
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (34 results)

All 2024 2023 2022 2021

All Journal Article (9 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 8 results,  Open Access: 4 results) Presentation (25 results) (of which Int'l Joint Research: 5 results,  Invited: 5 results)

  • [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

    • Related Report
      2023 Research-status Report
  • [Journal Article] Homeostasis and immunological function of self-driven memory-phenotype CD4+ T lymphocytes2023

    • Author(s)
      Kawabe T
    • Journal Title

      Immunol Med

      Volume: 46 Issue: 1 Pages: 1-8

    • DOI

      10.1080/25785826.2022.2129370

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Memory-phenotype CD4<sup>+</sup> 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
    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] IL-33-ILC2 axis promotes anti-tumor CD8+ T cell responses via OX40 signaling2022

    • 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

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] <i>Staphylococcus aureus</i> skin colonization promotes SLE-like autoimmune inflammation via neutrophil activation and the IL-23/IL-17 axis2022

    • 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

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Redefining the Foreign Antigen and Self-Driven Memory CD4+ T-Cell Compartments via Transcriptomic, Phenotypic, and Functional Analyses2022

    • 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

    • Related Report
      2022 Research-status Report
    • 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 differentiation2022

    • 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

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Memory-phenotype CD4+ T cells: a naturally arising T lymphocyte population possessing innate immune function.2022

    • Author(s)
      Kawabe T, Sher A.
    • Journal Title

      Int Immunol

      Volume: 34 Issue: 4 Pages: 189-196

    • DOI

      10.1093/intimm/dxab108

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Homeostasis of naive and memory T lymphocytes.2021

    • Author(s)
      Kawabe T, Yi J, Sprent J.
    • Journal Title

      Cold Spring Harb Perspect Biol

      Volume: 13 Issue: 9 Pages: a037879-a037879

    • DOI

      10.1101/cshperspect.a037879

    • Related Report
      2021 Research-status Report
    • 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
    • Related Report
      2023 Research-status Report
  • [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
    • Related Report
      2023 Research-status Report
  • [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
    • Related Report
      2023 Research-status Report
  • [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
    • Related Report
      2023 Research-status Report
  • [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
    • Related Report
      2023 Research-status Report
  • [Presentation] Redefining immunological significance of T cell self-reactivity.2023

    • Author(s)
      Takeshi Kawabe
    • Organizer
      第10回T cell seminar
    • Related Report
      2023 Research-status Report
    • 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
    • Related Report
      2023 Research-status Report
    • 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
    • Related Report
      2023 Research-status Report
    • 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
    • Related Report
      2023 Research-status Report
    • 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
    • Related Report
      2023 Research-status Report
    • 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
    • Related Report
      2022 Research-status Report
  • [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
    • Related Report
      2022 Research-status Report
  • [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
    • Related Report
      2022 Research-status Report
  • [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
    • Related Report
      2022 Research-status Report
  • [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
    • Related Report
      2022 Research-status Report
  • [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
    • Related Report
      2022 Research-status Report
  • [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
    • Related Report
      2022 Research-status Report
  • [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
    • Related Report
      2022 Research-status Report
  • [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
    • Related Report
      2022 Research-status Report
  • [Presentation] Memory-phenotype cells: naturally arising CD4+ T lymphocytes possessing innate immune function2022

    • 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
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] IL-12 derived from type 1 dendritic cells tonically promotes the differentiation of innate T-bethigh memory-phenotype CD4+ T lymphocytes in steady state.2021

    • Author(s)
      Kawabe T, Yi J, Kawajiri A, Hilligan K, Fang D, Ishii N, Yamane H, Zhu J, Jankovic D, Kim KS, Trinchieri G, Sher A.
    • Organizer
      第50回日本免疫学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] Inflammatory potential of self-driven memory-phenotype CD4+ T cells.2021

    • Author(s)
      Kawajiri A, Ishii M, Li J, Yang Z, Sato K, Tayama S, Okuyama Y, Harigae H, Ishii N, Kawabe T.
    • Organizer
      第50回日本免疫学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] Reactive sulfide species generated by cysteinyl-tRNA synthetase plays a regulatory role in T cell-induced colitis in a T cell-intrinsic manner.2021

    • Author(s)
      Tayama S, Kawabe T, Kitamura Y, Hiraide K, Li J, Yang Z, Kawajiri A, Sato K, Okuyama Y, Morita M, Akaike T, Ishii N.
    • Organizer
      第50回日本免疫学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 新規Tリンパ球「MP細胞」の恒常性維持機構の解明ならびにその自己免疫活性の究明.2021

    • Author(s)
      河部 剛史
    • Organizer
      第8回JCRベーシックリサーチカンファレンス
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 新たなCD4 T細胞「MP細胞」の産生・分化機構とその病理学的機能の解明.2021

    • Author(s)
      河部 剛史
    • Organizer
      第49回日本臨床免疫学会総会
    • Related Report
      2021 Research-status Report
    • Invited

URL: 

Published: 2021-03-19   Modified: 2024-12-25  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi