Molecular basis for the regulation of dendritic ell and mature T cell survival

• Project/Area Number: 22K08504
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kobe University
• Principal Investigator: 齊藤 泰之 神戸大学, 医学研究科, 講師 (40508842)
• Project Period (FY): 2022-04-01 – 2025-03-31
• Project Status: Granted (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2024: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 樹状細胞 / T細胞 / CD47 / SIRPα / 細胞死

Outline of Research at the Start

免疫応答の司令塔である樹状細胞（DC）は機能的に異なる複数の分画で構成され、そのうち２型古典的DC（cDC2）はヘルパーT細胞の活性化に重要な分画である。本研究では、cDC2に高度に発現するSIRPαとそのリガンドCD47による細胞間シグナル（CD47-SIRPαシグナル）を介したcDC2の機能制御に焦点を当て、CD47-SIRPαシグナルによるcDC2の生存制御機構に加え、cDC2による成熟T細胞の生存制御について研究を進める。本研究の成果は、免疫細胞の生存維持に機構に関する新たな分子基盤の解明や末梢T細胞腫瘍に対する新規治療法の開発へと繋がることが期待される。

Outline of Annual Research Achievements

樹状細胞（DC）は白血球に属し、自然免疫・獲得免疫双方に重要な役割を担っている。本研究では、DCのうち特にT細胞への抗原提示に重要である２型古典的DC（cDC2）に特異的に発現する受容体型膜タンパクSIRPαとそのリガンドCD47による細胞間シグナル（CD47-SIRPαシグナル）を介したcDC2の新たな制御機構を
明らかすることを目的とし、以下の2項目においてそれぞれ成果を得ることができた。
１）CD47-SIRPαシグナルによるcDC2生存制御機構の解明：前年度の結果よりSIRPαが分子Nの遺伝子発現を調節することでcDC2の生存を制御する可能性が考えられたため、新たにSIRPα/分子N二重欠損マウスを作成した。その結果、二重欠損マウスにおいてcDC2数の回復を認めたことから、上記仮説を個体レベルで証明することができた。今後は自己免疫疾患モデルを用いることでcDC2の機能回復が二重欠損マウスで認めるか検討を進める予定である。
２）cDC2による成熟T細胞の生存制御機構の解明：T細胞特異的にCD47を欠損させたマウスにおいて、末梢T細胞がcDC2によってプログラム細胞死の一種であるネクロトーシスが誘導された結果、末梢T細胞が著明に減少することを見出した。さらに、この細胞死の誘導にはcDC2上のSIRPαが重要であることから、cDC2上のSIRPαは末梢においてT細胞の監視および生存維持に重要であり、CD47欠損T細胞に対しては細胞死を誘導することで積極的な排除に関与することを明らかにし、PNAS誌に論文発表を行なった。

Current Status of Research Progress

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

Reason

課題２）においてはすでに成果をまとめて論文発表を行なっていることに加え、課題１）も投稿準備中であることからおおむね順調に進展していると判断するに至った。

Strategy for Future Research Activity

課題１に関してはSIRPα/分子N二重欠損マウスの個体レベルでの解析を引き続き進める予定である。

Research Products

• [Int'l Joint Research] バーゼル大学/チューリッヒ大学(スイス)
• [Int'l Joint Research] コロンビア大学(米国)
• [Int'l Joint Research] チューリッヒ大学(スイス)
• [Journal Article] Utility of the refined EBMT diagnostic and severity criteria 2023 for sinusoidal obstruction syndrome/veno-occlusive disease (2024)
  • Author(s): Ichikawa H, Yakushijin K, Kurata K, Tsuji T, Takemoto N, Joyce M, Okazoe Y, Takahashi R, Matsumoto S, Sakai R, Kitao A, Miyata Y, Saito Y, Kawamoto S, Yamamoto K, Ito M, Murayama T, Matsuoka H, Minami H
  • Journal Title: Bone Marrow Transplantation Volume: 59 Issue: 4 Pages: 518-525
  • DOI: 10.1038/s41409-024-02215-4
  • Peer Reviewed
• [Journal Article] Preclinical evaluation of the efficacy of an antibody to human SIRPα for cancer immunotherapy in humanized mouse models (2023)
  • Author(s): Saito Yasuyuki、Iida-Norita Rie、Afroj Tania、Refaat Alaa、Hazama Daisuke、Komori Satomi、Ohata Shinya、Takai Tomoko、Oduori Okechi S.、Kotani Takenori、Funakoshi Yohei、Koma Yu-Ichiro、Murata Yoji、Yakushijin Kimikazu、Matsuoka Hiroshi、Minami Hironobu、Yokozaki Hiroshi、Manz Markus G.、Matozaki Takashi
  • Journal Title: Frontiers in Immunology Volume: 14 Pages: 1294814-1294814
  • DOI: 10.3389/fimmu.2023.1294814
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer (2023)
  • Author(s): Omatsu Mayuki、Nakanishi Yuki、Kasashima Hiroaki、et al.
  • Journal Title: Nature Communications Volume: 14 Issue: 1 Pages: 5534-5534
  • DOI: 10.1038/s41467-023-41095-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lysosomal cholesterol overload in macrophages promotes liver fibrosis in a mouse model of NASH (2023)
  • Author(s): Itoh Michiko、Tamura Atsushi、Kanai Sayaka、Tanaka Miyako、Kanamori Yohei、Shirakawa Ibuki、Ito Ayaka、Oka Yasuyoshi、Hidaka Isao、Takami Taro、Honda Yasushi、Maeda Mitsuyo、Saito Yasuyuki、Murata Yoji、Matozaki Takashi、Nakajima Atsushi、Kataoka Yosky、Ogi Tomoo、Ogawa Yoshihiro、Suganami Takayoshi
  • Journal Title: Journal of Experimental Medicine Volume: 220 Issue: 11
  • DOI: 10.1084/jem.20220681
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Early diagnosis of sinusoidal obstruction syndrome after hematopoietic stem cell transplantation, with modified diagnostic criteria including refractory thrombocytopenia (2023)
  • Author(s): Ichikawa H, Yakushijin K, Miyata Y, Kanehira H, Joyce M, Hirakawa Y, Matsumoto S, Nagao S, Sakai R, Kurata K, Kitao A, Saito Y, Kawamoto S, Yamamoto K, Ito M, Murayama T, Matsuoka H, Minami H
  • Journal Title: eJHaem Volume: 4 Issue: 3 Pages: 695-704
  • DOI: 10.1002/jha2.728
  • Peer Reviewed / Open Access
• [Journal Article] CD47 promotes peripheral T cell survival by preventing dendritic cell?mediated T cell necroptosis (2023)
  • Author(s): Komori Satomi、Saito Yasuyuki、Nishimura Taichi、Respatika Datu、Endoh Hiromi、Yoshida Hiroki、Sugihara Risa、Iida-Norita Rie、Afroj Tania、Takai Tomoko、Oduori Okechi S.、Nitta Eriko、Kotani Takenori、Murata Yoji、Kaneko Yoriaki、Nitta Ryo、Ohnishi Hiroshi、Matozaki Takashi
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 120 Issue: 33 Pages: 1-1
  • DOI: 10.1073/pnas.2304943120
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Response to mRNA SARS‐CoV‐2 vaccination evaluated by B‐cell receptor repertoire after tixagevimab/cilgavimab administration (2023)
  • Author(s): Funakoshi Y, Yakushijin K, Ohji G, Matsutani T, Hojo W, Sakai H, Matsumoto S, Watanabe M, Kitao A, Saito Y, Kawamoto S, Yamamoto K, Koyama T, Nagatani Y, Kimbara S, Imamura Y, Kiyota N, Ito M, Minami H
  • Journal Title: British Journal of Haematology Volume: 202 Issue: 3 Pages: 504-516
  • DOI: 10.1111/bjh.18932
  • Peer Reviewed
• [Journal Article] Targeting of SIRPα as a potential therapy for Langerhans cell histiocytosis (2023)
  • Author(s): Okamoto Takeshi、Murata Yoji、Hasegawa Daiichiro、Yoshida Makiko、Tanaka Daisuke、Ueda Takashi、Hazama Daisuke、Oduori Okechi S.、Komori Satomi、Takai Tomoko、Saito Yasuyuki、Kotani Takenori、Kosaka Yoshiyuki、Maniwa Yoshimasa、Matozaki Takashi
  • Journal Title: Cancer Science Volume: - Issue: 5 Pages: 1871-1881
  • DOI: 10.1111/cas.15758
  • Peer Reviewed / Open Access
• [Journal Article] The Role of Type-2 Conventional Dendritic Cells in the Regulation of Tumor Immunity (2022)
  • Author(s): Saito Yasuyuki、Komori Satomi、Kotani Takenori、Murata Yoji、Matozaki Takashi
  • Journal Title: Cancers Volume: 14 Issue: 8 Pages: 1976-1976
  • DOI: 10.3390/cancers14081976
  • Peer Reviewed / Open Access
• [Journal Article] Global longitudinal strain is superior to ejection fraction for long‐term follow‐up after allogeneic hematopoietic stem cell transplantation (2022)
  • Author(s): Watanabe M, Yakushijin K, Tanaka H, Chijiki R, Saeki M, Hirakawa Y, Takakura H, Usui Y, Ichikawa H, Sakai R, Matsumoto S, Nagao S, Mizutani Y, Kurata K, Kitao A, Miyata Y, Saito Y, Kawamoto S, Yamamoto K, Ito M, Matsuoka H, Minami H
  • Journal Title: eJHaem Volume: 4 Issue: 1 Pages: 192-198
  • DOI: 10.1002/jha2.586
  • Peer Reviewed / Open Access
• [Journal Article] A Third Dose COVID-19 Vaccination in Allogeneic Hematopoietic Stem Cell Transplantation Patients (2022)
  • Author(s): Watanabe M, Yakushijin K, Funakoshi Y, Ohji G, Ichikawa H, Sakai H, Hojo W, Saeki M, Hirakawa Y, Matsumoto S, Sakai R, Nagao S, Kitao A, Miyata Y, Koyama T, Saito Y, Kawamoto S, Yamamoto K, Ito M, Murayama T, Matsuoka H, Minami H
  • Journal Title: Vaccines Volume: 10 Issue: 11 Pages: 1830-1830
  • DOI: 10.3390/vaccines10111830
  • Peer Reviewed / Open Access
• [Journal Article] Promising Efficacy of a Third Dose of mRNA SARS-CoV-2 Vaccination in Patients Treated with Anti-CD20 Antibody Who Failed 2-Dose Vaccination (2022)
  • Author(s): Funakoshi Y, Yakushijin K, Ohji G, Hojo W, Sakai H, Watanabe M, Kitao A, Miyata Y, Saito Y, Kawamoto S, Yamamoto K, Ito M, Koyama T, Imamura Y, Kiyota N, Matsuoka H, Mori Y, Minami H
  • Journal Title: Vaccines Volume: 10 Issue: 6 Pages: 965-965
  • DOI: 10.3390/vaccines10060965
  • Peer Reviewed / Open Access
• [Journal Article] The Safety and Immunogenicity of the BNT162b2 mRNA COVID-19 Vaccine in Japanese Patients after Allogeneic Stem Cell Transplantation (2022)
  • Author(s): Watanabe M, Yakushijin K, Funakoshi Y, Ohji G, Hojo W, Sakai H, Saeki M, Hirakawa Y, Matsumoto S, Sakai R, Nagao S, Kitao A, Miyata Y, Koyama T, Saito Y, Kawamoto S, Ito M, Murayama T, Matsuoka H, Minami H.
  • Journal Title: Vaccines Volume: 10 Issue: 2 Pages: 158-158
  • DOI: 10.3390/vaccines10020158
  • Peer Reviewed
• [Presentation] Preclinical evaluation of the efficacy of an antibody to human SIRPα for cancer immunotherapy in humanized mouse models. (2024)
  • Author(s): Saito Y, Tania A, Komori S, Takai T, Kotani T, Murata Y, Matozaki T
  • Organizer: The 5th Japan-Taiwan Bilateral Conference on Protein Phosphatase
  • Int'l Joint Research
• [Presentation] CD47 promotes peripheral T cell survival by preventing dendritic cell-mediated T cell necroptosis (2024)
  • Author(s): Saito Y, Komori S, Afroj T, Takai T, Oduori OS, Kotani T, Murata Y, Matozaki T
  • Organizer: Keystone symposia
  • Int'l Joint Research
• [Presentation] Preclinical evaluation of the efficacy of an antibody to human SIRPα for cancer immunotherapy in humanized mouse models (2023)
  • Author(s): Saito Y, Tania A, Komori S, Takai T, Oduori OS, Kotani T, Funakoshi Y, Murata Y, Yakushijin K, Matsuoka H, Minami H, Manz MG, Matozaki T
  • Organizer: 65th American society of hematology annual meeting
  • Int'l Joint Research
• [Presentation] CD47 promotes peripheral T cell survival by preventing dendritic cell-mediated T cell necroptosis (2023)
  • Author(s): Saito Y, Komori S, Afroj T, Takai T, Oduori OS, Nitta E, Kotani T, Murata Y, Nitta R, Matozaki T
  • Organizer: The 85th Annual Meeting of the Japanese Society of Hematology
• [Presentation] Preclinical evaluation of macrophage-targeted immunotherapy in vivo using a humanized mouse model (2023)
  • Author(s): Saito Y, Tania A, Iida-Norita R, Komori S, Takai T, Oduori OS, Kotani T, Koma Y, Murata Y, Yokozaki H, Matozaki T
  • Organizer: The 82nd Annual Meeting of the Japan Cancer Association
• [Presentation] Preclinical evaluation of macrophage-targeted immunotherapy in vivo using a humanized mouse model (2023)
  • Author(s): Saito Y, Tania A, Iida-Norita R, Komori S, Takai T, Oduori OS, Kotani T, Koma Y, Murata Y, Yokozaki H, Matozaki T
  • Organizer: The 2nd JCA-AACR Precision Cancer Medicine International Conference
• [Presentation] 新規ヒト化マウスを用いたマクロファージを介した抗腫瘍効果の前臨床評価モデル Preclinical evaluation of macrophage-mediated anti-tumor effct by using a novel humanized mouse model (2022)
  • Author(s): 齊藤泰之、飯田理恵、小森里美、小谷武徳、村田陽二、横崎宏、的崎尚
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] Dendritic cells regulate peripheral T cell survival through the CD47-SIRPαsignaling (2022)
  • Author(s): Yasuyuki Saito, Satomi Komori, Hiroki Yoshida, risa Sugihara, Tomoko Takai, Takenori Kotani, Yoji Murata, Takashi Matozaki
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] Preclinical evaluation of macrophage-mediated anti-tumor effects by using a humanized MITRG mouse model (2022)
  • Author(s): Yasuyuki Saito, Rie Iida-Norita, Afroj Tania, Satomi Komori, Takenori Kotani, Yoji Murata, Markus G Manz, Takashi Matozaki
  • Organizer: 6TH INTERNATIONAL WORKSHOP ON HUMANIZED MICE (IWHM6)
  • Int'l Joint Research
• [Presentation] Dendritic cells regulate peripheral T cell survival through the CD47-SIRPαsignaling (2022)
  • Author(s): Yasuyuki Saito, Satomi Komori, Hiroki Yoshida, Risa Sugihara, Takenori Kotani, Yoji Murata, Takashi Matozaki
  • Organizer: DC2022 国際樹状細胞学会
  • Int'l Joint Research
• [Presentation] SIRPα maintains cDC2 survival by regulating the Nr4a3 expression (2022)
  • Author(s): Satomi Komori, Yasuyuki Saito, Taichi Nishimura, Takenori Kotani, Yoji Murata, Takashi Matozaki
  • Organizer: DC2022 国際樹状細胞学会
• [Remarks] 神戸大学医学研究科 生体シグナル制御学部門（旧 シグナル統合学分野）ホームページ
  • URL: https://www.med.kobe-u.ac.jp/tougou/signal/Home.html
• [Remarks]
  • URL: https://www.med.kobe-u.ac.jp/tougou/signal/Home.html