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Fundamental research for the development of new immune response regulation methods targeting Foxp3 binding factor Ikzf1

Research Project

Project/Area Number 21H02748
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 49070:Immunology-related
Research InstitutionOsaka University

Principal Investigator

Ichiyama Kenji  大阪大学, 免疫学フロンティア研究センター, 特任准教授(常勤) (60777960)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2023: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2022: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2021: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
KeywordsIkzf1 / Foxp3 / 制御性T細胞 / 転写因子複合体 / 自己免疫疾患
Outline of Research at the Start

制御性T細胞 (Treg) は免疫自己寛容において中心的な役割を担う重要な細胞であり、Tregの免疫抑制機構の解明が現代免疫学の重要課題の一つとされている。これまで申請者はTregの免疫抑制機能に必須の転写因子であるFoxp3の新たな結合因子として転写因子Ikzf1を同定した。しかしながら、TregにおけるIkzf1の生理的意義は今のところ全く不明である。そこで本研究では、Treg特異的にIkzf1の機能不全変異体が発現する遺伝子改変マウスを用いて、Tregの免疫抑制機能におけるIkzf1の生理的役割を分子レベルで明らかにする。

Outline of Final Research Achievements

To develop the new immune disease therapies targeting regulatory T cells (Treg), we examined the role of the interaction between the transcription factors Foxp3 and Ikzf1 in Treg function. The disruption of the interaction between Foxp3 and Ikzf1 in Treg resulted in induction of epigenomic changes around Treg-related genes, which in turn disrupts Treg-specific gene expression patterns and Treg functional stability, leading to excessive immune responses and ultimately to the development of lethal autoimmune disease-like inflammation. Furthermore, Ikzf1 also played an important role in maintaining functional stability of human Treg.

Academic Significance and Societal Importance of the Research Achievements

正常個体中に存在する制御性T細胞(Treg)は、異常・過剰な免疫反応の抑制に特化したT細胞群であり、免疫自己寛容、免疫恒常性の維持に中心的な役割を果たしている。そしてその異常は、自己免疫病、アレルギー疾患、炎症性腸炎などの直接的原因となることが知られている。本研究成果は、Tregの機能安定性機構の基礎的理解を発展させた。今後、これら知見を基にヒトTregを標的とし、その量的・機能的増減による、がんや自己免疫疾患、移植臓器拒絶反応に対する新しい免疫応答制御法の開発、医療応用に繋がることが期待できる。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (7 results)

All 2024 2023 2022 2021 Other

All Int'l Joint Research (1 results) Journal Article (1 results) (of which Open Access: 1 results) Presentation (4 results) (of which Int'l Joint Research: 1 results) Patent(Industrial Property Rights) (1 results) (of which Overseas: 1 results)

  • [Int'l Joint Research] Harvard Medical School(米国)

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Ikzf1 association with Foxp3 for Foxp3-dependent gene repression in Treg cells: induction of autoimmunity and tumor immunity by disrupting the association2023

    • Author(s)
      Kenji Ichiyama, Jia Long, Yusuke Kobayashi, Yuji Horita, Takeshi Kinoshita, Yamami Nakamura, Chizuko Kominami, Katia Georgopoulos, Shimon Sakaguchi
    • Journal Title

      bioRxiv

      Volume: -

    • DOI

      10.1101/2023.08.12.553084

    • Related Report
      2023 Annual Research Report
    • Open Access
  • [Presentation] Ikzf1 association with Foxp3 for Foxp3-dependent gene repression in Treg cells: induction of autoimmunity by disrupting the association2024

    • Author(s)
      Kenji Ichiyama
    • Organizer
      Keystone Symposia, Systemic Autoimmune and Autoinflammatory Diseases (B2)
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Foxp3は転写因子Ikzf1との相互作用を介して制御性T細胞の機能安定性を制御する2024

    • Author(s)
      市山健司
    • Organizer
      日本薬学会第144年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Exon 5 of Ikzf1 is required for Foxp3-dependent gene suppression to maintain the homeostasis of regulatory T cells.2022

    • Author(s)
      Kenji Ichiyama
    • Organizer
      The 51st Annual Meeting of the Japanese Society for Immunology
    • Related Report
      2022 Annual Research Report
  • [Presentation] SRC2 and SRC3 cooperatively regulate Th17 cell development.2021

    • Author(s)
      市山健司
    • Organizer
      第50回日本免疫学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Patent(Industrial Property Rights)] 腫瘍の予防および/または治療剤2023

    • Inventor(s)
      市山健司、坂口志文、堀田裕司、木下武士
    • Industrial Property Rights Holder
      市山健司、坂口志文、堀田裕司、木下武士
    • Industrial Property Rights Type
      特許
    • Filing Date
      2023
    • Related Report
      2023 Annual Research Report
    • Overseas

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Published: 2021-04-28   Modified: 2025-01-30  

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