Reestablishing immune tolerance and homeostasis in autoimmune and autoinflammatory diseases

• Project/Area Number: 22K21354
• Research Category: Fund for the Promotion of Joint International Research (International Leading Research )
• Allocation Type: Multi-year Fund
• Review Section: Biological Sciences
• Research Institution: Osaka University
• Principal Investigator: 竹田 潔 大阪大学, 大学院医学系研究科, 教授 (20309446)
• Co-Investigator(Kenkyū-buntansha): 黒崎 知博 大阪大学, 免疫学フロンティア研究センター, 招へい教授 (50178125) ; 坂口 志文 大阪大学, 免疫学フロンティア研究センター, 特任教授(常勤) (30280770) ; 石井 優 大阪大学, 大学院生命機能研究科, 教授 (10324758) ; 茂呂 和世 大阪大学, 大学院医学系研究科, 教授 (90468489)
• Project Period (FY): 2022-12-20 – 2029-03-31
• Project Status: Granted (Fiscal Year 2024)
• Budget Amount: ¥689,000,000 (Direct Cost: ¥530,000,000、Indirect Cost: ¥159,000,000); Fiscal Year 2028: ¥104,000,000 (Direct Cost: ¥80,000,000、Indirect Cost: ¥24,000,000); Fiscal Year 2027: ¥104,000,000 (Direct Cost: ¥80,000,000、Indirect Cost: ¥24,000,000); Fiscal Year 2026: ¥104,000,000 (Direct Cost: ¥80,000,000、Indirect Cost: ¥24,000,000); Fiscal Year 2025: ¥104,000,000 (Direct Cost: ¥80,000,000、Indirect Cost: ¥24,000,000); Fiscal Year 2024: ¥104,000,000 (Direct Cost: ¥80,000,000、Indirect Cost: ¥24,000,000); Fiscal Year 2023: ¥104,000,000 (Direct Cost: ¥80,000,000、Indirect Cost: ¥24,000,000); Fiscal Year 2022: ¥65,000,000 (Direct Cost: ¥50,000,000、Indirect Cost: ¥15,000,000)
• Keywords: 免疫寛容 / 免疫疾患

Outline of Research at the Start

免疫系異常による疾患が近年急速に増加しつつある。これら疾患はQOLを低下させ致死にまで至らす。最近の研究は、これら疾患に関与する種々の免疫細胞亜集団を明らかにしてきている。従って次なる喫緊の課題は、「これら免疫細胞亜集団がどのようにして免疫病態に至るのかのメカニズム研究、その成果に基づき、免疫病態を予防・治療する革新的方法の開発」である。この課題解決のため、５人の日本サイド研究者が、トップレベルの臨床・基礎海外研究チームと強い連携・相互作用を介し学際的国際共同研究を展開する。又、この活動を通じて国際的競争力を有す若手研究者の育成を目指す。

Outline of Annual Research Achievements

本研究では、既に、免疫寛容・恒常性維持の基礎研究で国際的に大きな実績のある日本の５人の研究者が、海外研究チームと強い連携・相互作用して、より一層深い免疫寛容・過剰免疫の基礎メカニズムの解明、更に、海外臨床研究チームと共に、これら疾患を予防・治療する革新的治療法の開発を目指す。また、このプログラムを通じて、この分野に精通した将来の国際的競争力を有する若手研究者の育成を目指す。
竹田は、腸管免疫において、糖鎖転移酵素の腸管恒常性・免疫寛容における役割をスタンフォード大学との共同研究で検討しているが、２０２４年、種々の糖鎖構造の中で硫酸基付加が粘液バリアー機構維持に重要であることを見出した。坂口は英国バーミンガム大学との共同研究で、自己免疫性肝炎動物モデルで、独自に開発した誘導性制御T細胞の治療効果を確認した。バーミンガム大学からは、若手研究者を受け入れ技術移転を行った。黒崎は、オックスフォード大学へ若手研究者を1か月間派遣し、技術習得を行った。さらに、免疫寛容誘導に重要なIL-10がIgA長期生存プラズマ細胞で恒常的に発現していることを見出した。石井は関節リウマチ研究に関して、フランスマルセイユ研究所の研究グループと共同で研究を進め、フランスグループが樹立したマクロファージ栄養因子CSF1を種々の組織で欠損したマウスを用い、機能的に異なる個々のマクロファージの機能解析を行った。茂呂は肺線維症自然発症するIFNgR/Rag-2欠損マウスをモデルにして、ILC3がどのようなメカニズムで発症に関与しているかをオックスフォード大学との共同研究で明らかにした。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

上述しているように、５人の研究者ともに、研究課題は十分に絞られ、それぞれ確実な成果と新しい知見を得つつある。又、既に、海外研究チームの若手研究者を３か月、１か月という単位で受け入れ（坂口、黒崎）、逆に、１か月という単位で派遣し（黒崎、石井、茂呂）、それぞれのテーマに関しての相互的な議論・技術移転を行っている。更に、それぞれのグループでは、海外連携研究チームとオンライン会議を介して綿密な研究議論、国際会議への若手の派遣等、情報交換、議論の促進を図っており、国際的競争力を有する若手研究者の育成に十分留意して研究を推進している。

Strategy for Future Research Activity

竹田、坂口、石井、茂呂は、予定通り研究を遂行していく。黒崎は、長期生存IgAプラズマ細胞免疫寛容誘導に重要であることを見出したが、逆に免疫寛容破綻にはIgGプラズマ細胞が重要であるという予備的結果を得ている。IgGプラズマ細胞研究に関して、海外連携研究チームとしてセベロ・オチョア分子生物学センター（スペイン）・デューク大学（米国）も加え、新たな枠組みも更に構成する予定である。

Research Products

• [Int'l Joint Research] スタンフォード大学(米国)
• [Int'l Joint Research] バーミンガム大学/オックスフォード大学/University College London(英国)
• [Int'l Joint Research] Center d’Immunologie Marseille-Luminy(フランス)
• [Int'l Joint Research] ボン大学(ドイツ)
• [Int'l Joint Research] THSTI(インド)
• [Journal Article] Genome-wide CRISPR screen in human T cells reveals regulators of FOXP3 (2025)
  • Author(s): Chen Kelvin Y.、Kibayashi Tatsuya、Giguelay Ambre、Hata Mayu、Nakajima Shunsuke、Mikami Norihisa、Takeshima Yusuke、Ichiyama Kenji、Omiya Ryusuke、Ludwig Leif S.、Hattori Kunihiro、Sakaguchi Shimon
  • Journal Title: Nature Volume: online Issue: 8066 Pages: 191-200
  • DOI: 10.1038/s41586-025-08795-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] KLF2 expression in IgG plasma cells at their induction site regulates the migration program. (2025)
  • Author(s): Ise W, et al.
  • Journal Title: J Exp Med Volume: 222 Issue: 5
  • DOI: 10.1084/jem.20241019
  • Peer Reviewed / Open Access
• [Journal Article] Longitudinal analysis of immune responses to SARS-CoV-2 recombinant vaccine S-268019-b in phase 1/2 prime-boost study. (2025)
  • Author(s): Fujitani M, et al.
  • Journal Title: Front Immunol Volume: 16 Pages: 1550279-1550279
  • Peer Reviewed / Open Access
• [Journal Article] Intestinal Foxl1+ cell-derived CXCL12 maintains epithelial homeostasis by modulating cellular metabolism (2025)
  • Author(s): Yagita-Sakamaki Mayu、Ito Takayoshi、Sakaguchi Taiki、Shimma Shuichi、Li Bo、Okuzaki Daisuke、Motooka Daisuke、Nakamura Shota、Hase Koji、Fukusaki Eiichiro、Kikuchi Akira、Nagasawa Takashi、Kumanogoh Atsushi、Takeda Kiyoshi、Kayama Hisako
  • Journal Title: International Immunology Volume: 37 Issue: 4 Pages: 235-250
  • DOI: 10.1093/intimm/dxae068
  • Peer Reviewed / Open Access
• [Journal Article] Transcription factor Ikzf1 associates with Foxp3 to repress gene expression in Treg cells and limit autoimmunity and anti-tumor immunity (2024)
  • Author(s): Ichiyama Kenji、Long Jia、Kobayashi Yusuke、Horita Yuji、Kinoshita Takeshi、Nakamura Yamami、Kominami Chizuko、Georgopoulos Katia、Sakaguchi Shimon
  • Journal Title: Immunity Volume: 57 Issue: 9 Pages: 2043-2060
  • DOI: 10.1016/j.immuni.2024.07.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Csk restrains BCR-mediated ROS production and contributes to germinal center selection and affinity maturation. (2024)
  • Author(s): Inoue T, et al.
  • Journal Title: J Exp Med Volume: 221 Issue: 7
  • DOI: 10.1084/jem.20231996
  • Peer Reviewed / Open Access
• [Journal Article] Development of a new genotype-phenotype linked antibody screening system. (2024)
  • Author(s): Watanabe T, et al.
  • Journal Title: Elife Volume: 13
  • DOI: 10.7554/elife.95346
  • Peer Reviewed / Open Access
• [Journal Article] BCR signaling in germinal center B cell selection. (2024)
  • Author(s): Inoue T, Baba Y, Kurosaki T.
  • Journal Title: Trends Immunol Volume: 45 Issue: 9 Pages: 693-704
  • DOI: 10.1016/j.it.2024.07.005
  • Peer Reviewed / Open Access
• [Journal Article] Quantitative live-cell imaging of secretion activity reveals dynamic immune responses (2024)
  • Author(s): Yamagishi Mai、Miyata Kaede、Kamatani Takashi、Kabata Hiroki、Baba Rie、Tanaka Yumiko、Suzuki Nobutake、Matsusaka Masako、Motomura Yasutaka、Kiniwa Tsuyoshi、Koga Satoshi、Goda Keisuke、Ohara Osamu、Funatsu Takashi、Fukunaga Koichi、Moro Kazuyo、Uemura Sotaro、Shirasaki Yoshitaka
  • Journal Title: iScience Volume: 27 Issue: 6 Pages: 109840-109840
  • DOI: 10.1016/j.isci.2024.109840
  • Peer Reviewed / Open Access
• [Journal Article] NFκB dynamics-dependent epigenetic changes modulate inflammatory gene expression and induce cellular senescence. (2024)
  • Author(s): Tabata S, Matsuda K, Nagai K, Izumi Y, Takahashi M, Motomura Y, Ichikawa Nagasato A, Shimma S, Moro K, Bamba T, Okada M*.
  • Journal Title: The FEBS Journal Volume: 291(22) Issue: 22 Pages: 4951-4968
  • DOI: 10.1111/febs.17227
  • Peer Reviewed / Open Access
• [Journal Article] Cell-type specific, inducible and acute degradation of targeted protein in mice by two degron systems (2024)
  • Author(s): Yamashita Motoi、Ogawa Chihiro、Zhang Baihao、Kobayashi Tetsuro、Nomura Aneela、Barker Clive、Zou Chengcheng、Yamanaka Satoshi、Hayashi Ken-ichiro、Shinkai Yoichi、Moro Kazuyo、Fargarasan Sidonia、Imami Koshi、Seita Jun、Shirai Fumiyuki、Sawasaki Tatsuya、Kanemaki Masato T.、Taniuchi Ichiro
  • Journal Title: Nature Communications Volume: 15 Issue: 1 Pages: 10129-10129
  • DOI: 10.1038/s41467-024-54308-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The pyruvate-GPR31 axis promotes transepithelial dendrite formation in human intestinal dendritic cells. (2024)
  • Author(s): Oguro-Igashira E, Murakami M, Mori R, Kuwahara R, Kihara T, Kohara M, Fujiwara M, Motooka D, Okuzaki D, Arase M, Toyota H, Peng S, Ogino T, Kitabatake Y, Morii E, Hirota S, Ikeuchi H, Umemoto E, Kumanogoh A, Takeda K.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 121 Issue: 44
  • DOI: 10.1073/pnas.2318767121
  • Peer Reviewed / Open Access
• [Journal Article] The UDP-glucose/P2Y14 receptor axis promotes eosinophil-dependent large intestinal inflammation. (2024)
  • Author(s): Liu L, et al.
  • Journal Title: Int Immunol Volume: 36 Issue: 4 Pages: 155-166
  • DOI: 10.1093/intimm/dxad050
  • Peer Reviewed / Open Access
• [Journal Article] Differential dependence on microbiota of IL-23/IL-22-dependent gene expression between the small- and large-intestinal epithelia (2023)
  • Author(s): Nakatani A, et al.
  • Journal Title: Genes Cells Volume: 28 Issue: 11 Pages: 776-778
  • DOI: 10.1111/gtc.13065
  • Peer Reviewed / Open Access
• [Journal Article] Sialylation shapes mucus architecture inhibiting bacterial invasion in the colon. (2023)
  • Author(s): Taniguchi M,et al.
  • Journal Title: Mucosal Immunol. Volume: 16 Issue: 5 Pages: 624-641
  • DOI: 10.1016/j.mucimm.2023.06.004
  • Peer Reviewed / Open Access
• [Journal Article] Genomic repertoires linked with pathogenic potency of arthritogenic Prevotella copri isolated from the gut of patients with rheumatoid arthritis (2023)
  • Author(s): Nii Takuro、Maeda Yuichi、Motooka Daisuke、Naito Mariko、Matsumoto Yuki、Ogawa Takao、Oguro-Igashira Eri、Kishikawa Toshihiro、Yamashita Makoto、Koizumi Satoshi、Kurakawa Takashi、Okumura Ryu、Kayama Hisako、Murakami Mari、Sakaguchi Taiki、Das Bhabatosh、Nakamura Shota、Okada Yukinori、Kumanogoh Atsushi、Takeda Kiyoshi
  • Journal Title: Annals of the Rheumatic Diseases Volume: 82 Issue: 5 Pages: 621-629
  • DOI: 10.1136/ard-2022-222881
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Emerging roles of host and microbially derived bioactive lipids in inflammatory bowel diseases. (2023)
  • Author(s): Kayama H, Takeda K
  • Journal Title: Eur. J. Immunol. Volume: 53 Issue: 8
  • DOI: 10.1002/eji.202249866
  • Peer Reviewed / Open Access
• [Presentation] Regulation of IgM and IgG plasma cell fates (2025)
  • Author(s): Tomohiro Kurosaki
  • Organizer: Keystone Symposia, B Cells
  • Int'l Joint Research / Invited
• [Presentation] 制御性T細胞を標的とする免疫医療の展望 (2025)
  • Author(s): 坂口 志文
  • Organizer: NIBIOHNセミナー
  • Invited
• [Presentation] Conversion of disease-mediating T cells into Tregs for treatment of immunological diseases (2025)
  • Author(s): Shimon Sakaguchi
  • Organizer: The 3rd Keio University WPI-Bio2Q International Symposium
  • Int'l Joint Research / Invited
• [Presentation] Functions of two humoral memory populations and their generation mechanisms (2024)
  • Author(s): Tomohiro Kurosaki
  • Organizer: Seminar at School of Life Sciences, Peking University
  • Int'l Joint Research / Invited
• [Presentation] Homing of plasma cells to supportive niches (2024)
  • Author(s): Tomohiro Kurosaki
  • Organizer: EMBO Workshop: Lymphatic Tissues & Germinal Centres in Immune Reactions
  • Int'l Joint Research / Invited
• [Presentation] Fate decisions of germinal center (GC) B cells towards memory B cells and long-lived plasma cells (2024)
  • Author(s): Tomohiro Kurosaki
  • Organizer: Duke CHAVD (Consortia for HIV/AIDS Vaccine Development) 6th Annual Retreat
  • Int'l Joint Research / Invited
• [Presentation] Function of memory B cells and their generation mechanisms (2024)
  • Author(s): Tomohiro Kurosaki
  • Organizer: 16th Annual Meeting of Chinese Society for Immunology
  • Int'l Joint Research / Invited
• [Presentation] Function of memory B cells and their generation mechanisms (2024)
  • Author(s): Tomohiro Kurosaki
  • Organizer: 日独免疫ワークショップ
  • Int'l Joint Research / Invited
• [Presentation] Immune tolerance and regulatory T cells (2024)
  • Author(s): Shimon Sakaguchi
  • Organizer: Seminar at Charles University
  • Int'l Joint Research / Invited
• [Presentation] Induction of antigen-specific and functionally stable Tregs from effector/memory T cells for adoptive cell therapy of autoimmune disease (2024)
  • Author(s): Shimon Sakaguchi
  • Organizer: International LIT Symposium “Synthetic Immunology / Synthetic Biology
  • Int'l Joint Research / Invited
• [Presentation] Treg therapy of immunological diseases by converting disease-mediating T cells into Tregs (2024)
  • Author(s): Shimon Sakaguchi
  • Organizer: The 1st Annual Meeting of the Japanese Cytokine Society
  • Int'l Joint Research / Invited
• [Presentation] Targeting Regulatory T Cells (Tregs) in Cancer (2024)
  • Author(s): Shimon Sakaguchi
  • Organizer: The Science, Trials, and Future. 2024 ASCO Breakthrough
  • Int'l Joint Research / Invited
• [Presentation] Treg 2024 (2024)
  • Author(s): Shimon Sakaguchi
  • Organizer: The promise of Interleukin-2 Therapy
  • Int'l Joint Research / Invited
• [Presentation] Treatment of autoimmune disease by converting disease-mediating T cells into Treg cells (2024)
  • Author(s): Shimon Sakaguchi
  • Organizer: The 3rd UCL‐OU IFReC joint Symposium on Immunology
  • Int'l Joint Research / Invited
• [Presentation] 制御性Ｔ細胞による免疫疾患の制御 (2024)
  • Author(s): 坂口 志文
  • Organizer: 第52回日本臨床免疫学会総会
  • Invited
• [Presentation] Treatment of autoimmune disease by converting disease-mediating T cells into Treg cells (2024)
  • Author(s): Shimon Sakaguchi
  • Organizer: 日独免疫ワークショップ
  • Int'l Joint Research / Invited
• [Presentation] The Role of Group 2 Innate Lymphoid Cells in the Lung and Gut (2024)
  • Author(s): Kazuyo Moro
  • Organizer: FIMSAAdvanced Training Course 2023
  • Int'l Joint Research / Invited
• [Presentation] The role of group 2 innate lymphoid cells in ulcerative colitis (2024)
  • Author(s): Kazuyo Moro
  • Organizer: the 5th International Conference on Innate Lymphoid Cells
  • Int'l Joint Research / Invited
• [Presentation] The Role of Group 2 Innate Lymphoid Cells in Ulcerative Colitis (2024)
  • Author(s): Kazuyo Moro
  • Organizer: PORT for Health: Oncology 2024
  • Int'l Joint Research / Invited
• [Presentation] Mechanisms of Colitis Prevention Following Cecal Resection (2024)
  • Author(s): Kazuyo Moro
  • Organizer: Cytokines 2024
  • Int'l Joint Research / Invited
• [Presentation] Host-microbiota interaction for the maintenance of intestinal homeostasis. (2024)
  • Author(s): Kiyoshi Takeda
  • Organizer: KSM-KDCA Joint International Conference
  • Int'l Joint Research / Invited
• [Presentation] Host-microbiota interaction for intestinal homeostasis (2024)
  • Author(s): Kiyoshi Takeda
  • Organizer: 1st Symposium on Microbiome and Microbiome-based Therapeutics
  • Int'l Joint Research / Invited
• [Presentation] 腸内細菌と宿主の相互作用機構 (2024)
  • Author(s): 竹田潔
  • Organizer: 第75回日本皮膚科学会中部支部学術大会
  • Invited
• [Presentation] 腸内細菌と宿主の相互作用による消化管恒常性の維持機構 (2024)
  • Author(s): 竹田潔
  • Organizer: 日本外科代謝栄養学会第61回学術集会
  • Invited
• [Presentation] Host-microbiota interaction for the maintenance of intestinal homeostasis. (2024)
  • Author(s): Kiyoshi Takeda
  • Organizer: Naito Conference “Microbiome in Health and Disease”
  • Int'l Joint Research / Invited
• [Presentation] Host-microbiota interaction for the maintenance of intestinal homeostasis (2024)
  • Author(s): Kiyoshi Takeda
  • Organizer: KSBMB International Conference 2024
  • Int'l Joint Research / Invited
• [Presentation] Immunopathogenesis of IBD: Pathways and Therapeutic Challenges (2023)
  • Author(s): Kiyoshi Takeda
  • Organizer: International Psoriasis Council Global Seminar
  • Int'l Joint Research / Invited
• [Presentation] Host-microbiota interaction for intestinal homeostasis (2023)
  • Author(s): Kiyoshi Takeda
  • Organizer: 51st Annual Scientific Meeting of the Australian and New Zealand Society for Immunology
  • Int'l Joint Research / Invited
• [Presentation] 腸管炎症の制御機構の解析 (2023)
  • Author(s): 竹田潔
  • Organizer: 日本消化器免疫学
  • Invited
• [Presentation] 腸内細菌と宿主相互作用機構 (2023)
  • Author(s): 竹田潔
  • Organizer: 日本神経消化器学会
  • Invited
• [Presentation] 腸内細菌と宿主相互作用機構 (2023)
  • Author(s): 竹田潔
  • Organizer: 腸内細菌学会
  • Invited