Study for Establishment of Novel SLE Therapy by Induction of Follicular Regulatory T Cell Differentiation

• Project/Area Number: 20K08797
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Chiba University
• Principal Investigator: SUZUKI KOTARO 千葉大学, 大学院医学研究院, 准教授 (90554634)
• Co-Investigator(Kenkyū-buntansha): 須藤 明 千葉大学, 大学院医学研究院, 准教授 (50447306) ; 岩本 太郎 千葉大学, 医学部附属病院, 助教 (80835083)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Tfr細胞 / SLE / Ascl2 / 濾胞性制御性T細胞 / 全身性エリテマトーデス / 濾胞制御性T細胞

Outline of Research at the Start

SLEでは、DNAや核蛋白質などが主要な自己抗原と考えられているが、これらの一部はendosomal toll-like receptor (TLR3/7/8/9)のagonistでもあり、SLEの病態形成、炎症増悪におけるendosomal TLR依存性シグナルの重要性が示唆されている。そこで本申請研究では、TLR7 agonistであるimiquimodを用いたimiquimod誘導性ループスモデル をSLEのモデルマウスとして使用し、Tfr細胞分化におけるAscl2の役割とSLEの病態形成におけるTreg細胞内Ascl2の役割を明らかにする。

Outline of Final Research Achievements

T follicular regulatory (Tfr) cells, a subset of Treg, locate to the lymphoid follicle and GC and regulate antibody responses. CD25- mature Tfr cells differentiate from CD25+ Treg cells through CD25+ immature Tfr cells. Others and we have shown that Ascl2 plays a role in Tfh cell development; however, the role of Ascl2 in the development of Tfr cells remains unclear. Here, I found that Ascl2 was highly and preferentially expressed in CD25+ Tfr cells and CD25- Tfr cells, and that the differentiation from CD25+ Tfr cells to CD25- Tfr cells was impaired by the absence of Ascl2. Furthermore, the forced Ascl2 expression in Treg cells downregulated CD25 expression and suppressed IL-2-induced phosphorylation of STAT5, which is known to suppress CD25- Tfr cell development. These results suggest that Ascl2 plays a vital role in developing Tfr cells.

Academic Significance and Societal Importance of the Research Achievements

本申請研究においては、FOXP3-Cre x Ascl2fl/flマウスを作成し、Tfr細胞分 化やimiquimod誘導性ループスの病態形成におけるTfr細胞内Ascl2の役割を明らかにした。本研究成果により、今後Ascl2 を標的とした Tfr細胞/Tfh細胞バランスの制御による新たなSLE治療法確立のための基盤が 構築されることが期待される。

Research Products

• [Journal Article] Epithelial cell-derived cytokine TSLP modulates metabolic program of regulatory T cells by enhancing fatty acid uptake to suppress the intestinal inflammation (2023)
  • Author(s): Kasuya T., Tanaka S., Etori K., Shoda J., Hattori K., Endo Y., Kitajima M., Kageyama T., Iwamoto T., Yokota M., Iwata A., Suto A., Suzuki K., Suzuki H., Ziegler SF., and Nakajima H
  • Journal Title: Sci. Rep. Volume: 13 Issue: 1 Pages: 1653-1653
  • DOI: 10.1038/s41598-023-28987-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Relationship of systemic type I interferon activity with clinical phenotypes, disease activity, and damage accrual in systemic lupus erythematosus in treatment-naive patients: a retrospective longitudinal analysis (2023)
  • Author(s): Miyachi Kazusa、Iwamoto Taro、Kojima Shotaro、Ida Tomoaki、Suzuki Junya、Yamamoto Takuya、Mimura Norihiro、Sugiyama Takahiro、Tanaka Shigeru、Furuta Shunsuke、Ikeda Kei、Suzuki Kotaro、Niewold Timothy B.、Nakajima Hiroshi
  • Journal Title: Arthritis Research & Therapy Volume: 25 Issue: 1 Pages: 1-13
  • DOI: 10.1186/s13075-023-03010-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Semaphorin 3G exacerbates joint inflammation through the accumulation and proliferation of macrophages in the synovium (2022)
  • Author(s): Shoda Jumpei、Tanaka Shigeru、Etori Keishi、Hattori Koto、Kasuya Tadamichi、Ikeda Kei、Maezawa Yuko、Suto Akira、Suzuki Kotaro、Nakamura Junichi、Maezawa Yoshiro、Takemoto Minoru、Betsholtz Christer、Yokote Koutaro、Ohtori Seiji、Nakajima Hiroshi
  • Journal Title: Arthritis Research & Therapy Volume: 24 Issue: 1 Pages: 134-134
  • DOI: 10.1186/s13075-022-02817-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Antiphospholipid antibody positivity and the thrombotic risk in Japanese patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (2022)
  • Author(s): Suzuki Junya、Furuta Shunsuke、Sugiyama Takahiro、Iwamoto Taro、Ikeda Kei、Suzuki Kotaro、Nakajima Hiroshi
  • Journal Title: Modern Rheumatology Volume: 33 Issue: 2 Pages: 346-351
  • DOI: 10.1093/mr/roac031
  • Peer Reviewed
• [Journal Article] Suppressor of cytokine signalling 3 (SOCS3) expressed in podocytes attenuates glomerulonephritis and suppresses autoantibody production in an imiquimod-induced lupus model (2021)
  • Author(s): Fukuta M, Suzuki K, Kojima S, Yabe Y, Suzuki K, Iida K, Yamada H, Makino S, Iwata A, Tanaka S, Iwamoto T, Suto A, Nakagomi D, Wakashin H, Maezawa Y, Maezawa Y, Takemoto M, Asanuma K, Nakajima H.
  • Journal Title: Lupus Sci Med. Volume: 8 Issue: 1 Pages: 426-426
  • DOI: 10.1136/lupus-2020-000426
  • Peer Reviewed / Open Access
• [Journal Article] NF-κB1 Contributes to Imiquimod-Induced Psoriasis-Like Skin Inflammation by Inducing Vγ4 + Vδ4 + γδT17 Cells (2021)
  • Author(s): Suzuki K, Suzuki K, Yabe Y, Iida K, Ishikawa J, Makita S, Kageyama T, Iwamoto T, Tanaka S, Yokota M, Iwata A, Suto A, Nakajima H.
  • Journal Title: J Invest Dermatol. Volume: 22 Issue: 6 Pages: 22-22
  • DOI: 10.1016/j.jid.2021.11.004
  • Peer Reviewed
• [Journal Article] Experience of musculoskeletal ultrasound scanning improves physicians’ physical examination skills in assessment of synovitis (2020)
  • Author(s): Saku Aiko, Furuta Shunsuke, Kato Manami, Furuya Hiroki, Suzuki Kazumasa, Fukuta Masashi, Suehiro Kenichi, Makita Sohei, Tamachi Tomohiro, Ikeda Kei, Takatori Hiroaki, Maezawa Yuko, Suto Akira, Suzuki Kotaro, Hirose Koichi, Nakajima Hiroshi.
  • Journal Title: Clinical Rheumatology Volume: 39 Issue: 4 Pages: 1091-1099
  • DOI: 10.1007/s10067-020-04960-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] RNA-Binding Protein ZFP36L2 Downregulates Helios Expression and Suppresses the Function of Regulatory T Cells. (2020)
  • Author(s): Makita S, Takatori H, Iwata A, Tanaka S, Furuta S, Ikeda K, Suto A, Suzuki K, Ramos SBV, Nakajima H.
  • Journal Title: Front Immunol. Volume: 11 Pages: 1291-1300
  • DOI: 10.3389/fimmu.2020.01291
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] High Type I Interferon Activity is Associated with the Pathogenesis of SLE and the Accrual of Organ Damage in Japanese SLE Patients (2022)
  • Author(s): Kazusa Miyachi, Taro Iwamoto, Shotaro Kojima, Norihiro Mimura, Takuya Yamamoto, Junya Suzuki, Takahiro Sugiyama, Shunsuke Furuta, Kei Ikeda, Kotaro Suzuki, Hiroshi Nakajima
  • Organizer: 日本リウマチ学会総会学術集会