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Mechanisms of adaptive immune regulation by regulatory T cells

Research Project

Project/Area Number 21H04801
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 49:Pathology, infection/immunology, and related fields
Research InstitutionThe University of Tokyo

Principal Investigator

Hori Shohei  東京大学, 大学院薬学系研究科(薬学部), 教授 (50392113)

Project Period (FY) 2021-04-05 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥42,510,000 (Direct Cost: ¥32,700,000、Indirect Cost: ¥9,810,000)
Fiscal Year 2023: ¥12,220,000 (Direct Cost: ¥9,400,000、Indirect Cost: ¥2,820,000)
Fiscal Year 2022: ¥12,220,000 (Direct Cost: ¥9,400,000、Indirect Cost: ¥2,820,000)
Fiscal Year 2021: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
Keywords制御性T細胞 / 自己免疫疾患 / 免疫寛容 / 免疫制御 / T細胞受容体 / 転写因子 / 遺伝子発現制御
Outline of Research at the Start

免疫抑制機能を持つ制御性T細胞(Treg)は、組織環境の変化に応じて可塑的に遺伝子発現を変化させて適応的に応答することにより、様々な病的免疫応答から自己組織を守っている。我々はこれまでに、Tregが組織環境において適応的に免疫応答を制御するためには、Tregのマスター転写因子Foxp3とT細胞受容体シグナルが協同することが重要であることを見いだしている。本研究ではこの独自の発見を手がかりとしてTregの適応的免疫制御機構を解明することを目指す。

Outline of Final Research Achievements

In this study, we sought to elucidate the molecular basis of regulatory T (Treg) cell "adaptability", the ability to adapt and function in changing immune and tissue environments. Using knock-in mice harboring the Foxp3 A384T mutation, which impairs Treg cell accumulation in a tissue-restricted manner, we demonstrated that this mutation impairs the clonal expansion and tissue infiltration of effector Treg cells that receive strong TCR signals, thereby reducing the number of effector Treg cells in specific tissues. At the molecular level, this Foxp3 mutation impairs TCR-induced c-Myc upregulation in effector Treg cells and thereby their cell proliferation. In addition, our results suggest that Foxp3 promotes Treg activation and effector differentiation in cooperation with several transcription factors downstream of TCR signaling.

Academic Significance and Societal Importance of the Research Achievements

本研究により、Tregが免疫抑制機能を発現して自己免疫寛容を確立・維持するうえで、TregがTCRを介して組織抗原を認識することでエフェクター型Tregに分化し、クローン増殖して組織内に浸潤して組織環境に適応することが重要であることを明らかにした。そして、Tregの適応性を制御する分子機構の一端を解明した。これらの知見はTregによる免疫制御機構の新たな側面を解明したばかりでなく、組織選択的な自己免疫疾患の発症機序の理解や治療戦略の開発にもつながる可能性がある。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Comments on the Screening Results   Annual Research Report
  • Research Products

    (38 results)

All 2024 2023 2022 2021 Other

All Journal Article (10 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 10 results,  Open Access: 8 results) Presentation (27 results) (of which Int'l Joint Research: 3 results,  Invited: 10 results) Remarks (1 results)

  • [Journal Article] Diet-mediated constitutive induction of novel IL4+ ILC2 cells maintains intestinal homeostasis in mice2023

    • Author(s)
      Cui Wanlin, Nagano Yuji, Hatakeyama Masanori, Honda Kenya , et al.
    • Journal Title

      Journal of Experimental Medicine

      Volume: - Issue: 8

    • DOI

      10.1084/jem.20221773

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cathepsin W restrains peripheral regulatory T cells for mucosal immune quiescence2023

    • Author(s)
      Li Jian, Chen Zuojia, Kim Girak, Luo Jialie, Hori Shohei, Wu Chuan
    • Journal Title

      Science Advances

      Volume: 9 Issue: 28

    • DOI

      10.1126/sciadv.adf3924

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Functional analysis of Foxp3 and its mutants by retroviral transduction of murine primary CD4(+) T Cells.2023

    • Author(s)
      Nakajima A, Murakami R, Hori S
    • Journal Title

      Methods in Molecular Biology

      Volume: 2559 Pages: 79-94

    • DOI

      10.1007/978-1-0716-2647-4_7

    • ISBN
      9781071626467, 9781071626474
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Neuropilin-1 (NRP1) expression distinguishes self-reactive helper T cells in systemic autoimmune disease.2022

    • Author(s)
      Raveney BJ, El-Darawish Y, Sato W, Arinuma Y, Yamaoka K, Hori S, Yamamura T, Oki S
    • Journal Title

      EMBO Molecular Medicine

      Volume: 14 Issue: 10 Pages: 1-20

    • DOI

      10.15252/emmm.202215864

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Whole-embryonic identification of maternal microchimeric cell types in mouse using single-cell RNA sequencing2022

    • Author(s)
      Fujimoto Kana、Nakajima Akira、Hori Shohei、Tanaka Yumiko、Shirasaki Yoshitaka、Uemura Sotaro、Irie Naoki
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 18313-18313

    • DOI

      10.1038/s41598-022-20781-9

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Peripheral tolerance by Treg via constraining OX40 signal in autoreactive T cells against desmoglein 3, a target antigen in pemphigus2021

    • Author(s)
      Iriki H, et al.
    • Journal Title

      Proc Natl Acad Sci USA

      Volume: 118 Issue: 49

    • DOI

      10.1073/pnas.2026763118

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Whole embryonic detection of maternal microchimeric cells highlights significant differences in their numbers among individuals2021

    • Author(s)
      Fujimoto K, et al.
    • Journal Title

      Plos one

      Volume: 16 Issue: 12 Pages: 1-11

    • DOI

      10.1371/journal.pone.0261357

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The adaptability of regulatory T cells and Foxp32021

    • Author(s)
      Hori S and Murakami R
    • Journal Title

      Int Immunol

      Volume: 33 Issue: 12 Pages: 803-807

    • DOI

      10.1093/intimm/dxab045

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] FOXP3 as a master regulator of Treg cells2021

    • Author(s)
      Hori S
    • Journal Title

      Nat Rev Immunol

      Volume: 21 Issue: 10 Pages: 618-619

    • DOI

      10.1038/s41577-021-00598-9

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Regulatory T Cell Heterogeneity: Canonical and Non-Canonical Functions.2021

    • Author(s)
      Sefik E, Hori S, Vasanthakumar A
    • Journal Title

      Front Immunol

      Volume: 12 Pages: 722563-722563

    • DOI

      10.3389/fimmu.2021.722563

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Regulation of T cell responses in health and disease2024

    • Author(s)
      Shohei Hori
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 制御性T細胞とアレルギー2024

    • Author(s)
      堀昌平
    • Organizer
      日本アレルギー学会 第10回総合アレルギー講習会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] GATA3 dysfunction in follicular regulatory T cells may underlie selective dysregulation of type 2 humoral immunity in Foxp3A384T mice2024

    • Author(s)
      Shiki Masumoto, Akira Nakajima, Shohei Hori
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Inhibition of AKT-mTOR signaling contributes to Foxp3-dependent induction of endogenous Foxp3 transcription in vivo2024

    • Author(s)
      Yuxi Wei, Hinako Ago, Shotaro Funatsu, Ryuichi Murakami, Akira Nakajima, Shohei Hori
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] MHC class II limits microbiota-dependent activation of colonic CD8 T cells in a CD4 T cell- and LAG-3- dependent manner2024

    • Author(s)
      Tomoya Sengiku, Masato Kubo, Shohei Hori, Ruka Setoguchi
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Overexpression of BATF enhances proliferative and suppressive activities of Treg cells in vivo2024

    • Author(s)
      Kohta Matsuura, Ryuichi Murakami, Shohei Hori
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Foxp3A384T mutation represses Myc transcription without globally affecting chromatin accessibility in effector Treg cells2024

    • Author(s)
      Suzu Kawagoe, Ryuichi Murakami, Shohei Hori
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] T cell receptor repertoires of regulatory and conventional T cells converge during differentiation into effector or memory states2024

    • Author(s)
      Reiko Tsukazaki, Ryuichi Murakami, Shohei Hori
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 生体内におけるFoxp3依存的な内在性Foxp3の発現誘導メカニズム: AKT-mTOR経路抑制の寄与2023

    • Author(s)
      魏宇熙、吾郷日向子、船津翔太郎、村上龍一、中島啓、堀昌平
    • Organizer
      第32回Kyoto T Cell Conference
    • Related Report
      2023 Annual Research Report
  • [Presentation] TCR-mTORC1経路依存的なTreg固有のエピゲノム形成機構2023

    • Author(s)
      木下誠秀、大野真衣、早津徳人、大西玲子、中島啓、堀昌平
    • Organizer
      第32回Kyoto T Cell Conference
    • Related Report
      2023 Annual Research Report
  • [Presentation] MHCクラスII分子はCD4とLAG-3に依存して大腸CD8 T細胞の活性化 を制御する2023

    • Author(s)
      千菊智也、久保允人、堀昌平、瀬戸口留可
    • Organizer
      第32回Kyoto T Cell Conference
    • Related Report
      2023 Annual Research Report
  • [Presentation] Molecular control of Treg cell differentiation and function by Foxp3 and TCR signals.2022

    • Author(s)
      Shohei Hori
    • Organizer
      2022 FIMSA Advanced Immunology Course
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Molecular control of Treg cell function by Foxp3 and TCR signals.2022

    • Author(s)
      Shohei Hori
    • Organizer
      ImmunOctoberfest 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Control of regulatory T cell differentiation and function by the transcription factor Foxp3 and the T cell receptordependent recognition of immunological self.2022

    • Author(s)
      Shohei Hori
    • Organizer
      第95回日本生化学会大会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Molecular control of Treg cell differentiation and function by Foxp3 and TCR signals.2022

    • Author(s)
      Shohei Hori
    • Organizer
      第51回日本免疫学会学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Foxp3 A384T変異は制御性T 細胞のTCR 刺激依存的な増殖をBatf発現抑制非依存的に障害する2022

    • Author(s)
      川越紗,村上龍一,堀昌平
    • Organizer
      第31回Kyoto T Cell Conference
    • Related Report
      2022 Annual Research Report
  • [Presentation] 制御性T細胞選択的BATF発現増強マウスの解析2022

    • Author(s)
      松浦宏大,村上龍一,堀昌平
    • Organizer
      第31回Kyoto T Cell Conference
    • Related Report
      2022 Annual Research Report
  • [Presentation] MHCクラスII分子はCD4 T細胞非依存的に大腸CD8 T細胞の活性化を制御する2022

    • Author(s)
      千菊智也,堀昌平,瀬戸口留可
    • Organizer
      第21回次世代を担う若手のためのファーマ・バイオフォーラム2022
    • Related Report
      2022 Annual Research Report
  • [Presentation] The Foxp3 A384T mutation impairs TCR-induced proliferation of effector regulatory T cells by interfering with c-Myc induction2022

    • Author(s)
      Suzu Kawagoe, Maori Oda, Ryuichi Murakami, Shohei Hori
    • Organizer
      第51回日本免疫学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Robust TCR signals control epigenetic conversion of conventional T cells to regulatory T cells through mTORC1-dependent expression of TET proteins2022

    • Author(s)
      Tomohide Kinoshita, Mai Ohno, Norihito Hayatsu, Reiko Ohnishi, Akira Nakajima, Shohei Hori
    • Organizer
      第51回日本免疫学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Tissue-specific deficiency of clonally expanded regulatory T cells underlies tissue-restricted inflammation in Foxp3 A384T mutant mice2022

    • Author(s)
      Yoshimichi Hoshiya, Ryuichi Murakami, Shohei Hori
    • Organizer
      第51回日本免疫学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Foxp3-transduced T cells acquire regulatory T cell-like epigenome, gene expression, and suppressive activity in vivo2022

    • Author(s)
      Yuxi Wei, Shotaro Funatsu, Ryuichi Murakami, Akira Nakajima, Shohei Hori
    • Organizer
      第51回日本免疫学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] BATF-overexpressing Treg cells show enhanced tissue accumulation and suppressive ability in vivo2022

    • Author(s)
      Kohta Matsuura, Akihiko Kimura, Takahisa Miyao, Ryuichi Murakami, Shohei Hori
    • Organizer
      第51回日本免疫学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 制御性T細胞による免疫制御メカニズム2022

    • Author(s)
      堀昌平
    • Organizer
      第46回皮膚科免疫セミナー
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Molecular control of Treg cell function by Foxp3 and TCR signals2021

    • Author(s)
      Hori S
    • Organizer
      Hong Kong Immunology Forum 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 組織Tregによる組織選択的2型炎症制御機構2021

    • Author(s)
      堀昌平
    • Organizer
      第85回日本インターフェロン・サイトカイン学会学術集会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Tregとアレルギー2021

    • Author(s)
      堀昌平
    • Organizer
      日本アレルギー学会 第7回総合アレルギー講習
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Remarks] 東京大学大学院薬学系研究科免疫・微生物学教室ホームページ

    • URL

      https://meneki.f.u-tokyo.ac.jp/

    • Related Report
      2023 Annual Research Report

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

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