A molecular basis of inflammatory Th17 cells in autoimmune diseases

• Project/Area Number: 16H06233
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Immunology
• Research Institution: Kyoto University
• Principal Investigator: Hirota Keiji 京都大学, ウイルス・再生医科学研究所, 准教授 (90631250)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥25,090,000 (Direct Cost: ¥19,300,000、Indirect Cost: ¥5,790,000); Fiscal Year 2018: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2017: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2016: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
• Keywords: Th17細胞 / 自己免疫疾患モデル / Th17 / GM-CSF / 自己免疫性関節炎 / IL-17

Outline of Final Research Achievements

In this study, we investigated an inflammatory cascade mediated by autoimmune Th17 cells and analyzed inflammatory networks starting from Th17 cells and their constituent factors. In particular, we elucidated the significance and regulatory mechanism of GM-CSF-producing inflammatory subsets in autoimmune arthritis, and identified synovial innate lymphoid cells that highly produced GM-CSF, a novel arthritogenic inflammatory subset. We also identified Satb1 as a molecule involved in the regulation of an effector gene expression network in autoimmune Th17 cells. These results advanced our understanding of how chronic inflammation is maintained by the interaction between immune cells and mesenchymal cells.

Academic Significance and Societal Importance of the Research Achievements

本研究では、炎症性Th17細胞を起点とした炎症局所における細胞間相互作用とその制御因子を明らかにした。今後、これらの成果を標的とした次世代の予防法・治療法開発にも研究展開が可能である。GM-CSF阻害剤を用いた治験では関節リウマチに対する高い有効性が報告されており、今後、GM-CSFを産生する自然リンパ球を標的とした治療薬開発も期待できる。また、Satb1を標的とした炎症性Th17細胞の制御法の確立は、Th17細胞が起こす自己免疫疾患に対する免疫学的な新規治療法になりうる可能性がある。

Research Products

• [Int'l Joint Research] Institute of Molecular Health Sciences(スイス)
• [Int'l Joint Research] The Francis Crick Institute/The University of Edinburgh(英国)
• [Int'l Joint Research] The University of Edinburgh/The Francis Crick Institute(英国)
• [Int'l Joint Research] ETH Zurich(Switzerland)
• [Journal Article] Correction to: The pathogenicity of Th17 cells in autoimmune diseases (2019)
  • Author(s): Yasuda Keiko、Takeuchi Yusuke、Hirota Keiji
  • Journal Title: Seminars in Immunopathology Volume: 41 Issue: 3 Pages: 299-299
  • DOI: 10.1007/s00281-019-00746-3
  • Peer Reviewed
• [Journal Article] Satb1 regulates the effector program of encephalitogenic tissue Th17 cells in chronic inflammation (2019)
  • Author(s): Yasuda Keiko、Kitagawa Yohko、Kawakami Ryoji、Isaka Yoshitaka、Watanabe Hitomi、Kondoh Gen、Kohwi-Shigematsu Terumi、Sakaguchi Shimon、Hirota Keiji
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 549-549
  • DOI: 10.1038/s41467-019-08404-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 自己免疫性関節炎を惹起するTh17細胞を起点とした炎症カスケード (2019)
  • Author(s): 廣田 圭司
  • Journal Title: 臨床免疫・アレルギー科 Volume: 71 Pages: 1-7
• [Journal Article] Autoimmune Th17 Cells Induced Synovial Stromal and Innate Lymphoid Cell Secretion of the Cytokine GM-CSF to Initiate and Augment Autoimmune Arthritis (2018)
  • Author(s): Hirota Keiji、Hashimoto Motomu、Ito Yoshinaga、Matsuura Mayumi、Ito Hiromu、Tanaka Masao、Watanabe Hitomi、Kondoh Gen、Tanaka Atsushi、Yasuda Keiko、Kopf Manfred、Potocnik Alexandre J.、Stockinger Brigitta、Sakaguchi Noriko、Sakaguchi Shimon
  • Journal Title: Immunity Volume: 48 Issue: 6 Pages: 1220-1232
  • DOI: 10.1016/j.immuni.2018.04.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical and Histopathological Amelioration of Experimental Autoimmune Encephalomyelitis by AAV Vectors Expressing a Soluble Interleukin-23 Receptor (2017)
  • Author(s): Miralles Marta、Eixarch Herena、Tejero Marcos、Costa Carme、Hirota Keiji、Casta?o A. Raul、Puig Meritxell、Stockinger Gitta、Montalban Xavier、Bosch Assumpci?、Espejo Carmen、Chillon Miguel
  • Journal Title: Neurotherapeutics Volume: 14 Issue: 4 Pages: 1095-1106
  • DOI: 10.1007/s13311-017-0545-8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment. (2017)
  • Author(s): Kitagawa Y, Ohkura N, Kidani Y, Vandenbon A, Hirota K, Kawakami R, Yasuda K, Motooka D, Nakamura S, Kondo M, Taniuchi I, Kohwi-Shigematsu T, Sakaguchi S.
  • Journal Title: Nat Immunol. Volume: 18(2) Issue: 2 Pages: 173-183
  • DOI: 10.1038/ni.3646
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine. (2016)
  • Author(s): Maeda Y, Kurakawa T, Umemoto E, Motooka D, Ito Y, Gotoh K, Hirota K, Matsushita M, Furuta Y, Narazaki M, Sakaguchi N, Kayama H, Nakamura S, Iida T, Saeki Y, Kumanogoh A, Sakaguchi S, and Takeda K
  • Journal Title: Arthritis Rheum Volume: 68 Issue: 11 Pages: 2646-2661
  • DOI: 10.1002/art.39783
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 自己免疫性関節炎を惹起するヘルパーTサブセットと認識自己抗原 (2016)
  • Author(s): 廣田圭司
  • Journal Title: 最新医学 Volume: 71 Pages: 2320-2325
• [Presentation] Inflammatory cascade of autoimmune arthritis by Th17 cells and GM-CSF-producing ILCs (2019)
  • Author(s): Hirota K, Hashimoto M, Ito Y, Matsuura M, Ito H, Tanaka M, Watanabe H, Kondoh G, Tanaka A, Yasuda K, Kopf M, Potocnik AJ, Stockinger B, Sakaguchi N, Sakaguchi S
  • Organizer: Keystone symposium
  • Int'l Joint Research
• [Presentation] An inflammatory cellular cascade of autoimmune Th17 cells, GM-CSF-producing synovial ILCs and stromal cells in the development of autoimmune arthritis (2018)
  • Author(s): Hirota K, Hashimoto M, Ito Y, Matsuura M, Ito H, Tanaka M, Watanabe H, Kondoh G, Tanaka A, Yasuda K, Kopf M, Potocnik AJ, Stockinger B, Sakaguchi N, Sakaguchi S
  • Organizer: Kyoto T cell Conference
  • Int'l Joint Research
• [Presentation] Autoimmune arthritis mediated by inflammatory Th17 cells (2018)
  • Author(s): Keiji Hirota
  • Organizer: 25th East Asia Joint Symposium
  • Int'l Joint Research / Invited
• [Presentation] Satb1-mediated regulation of GM-CSF and PD-1 in pathogenic Th17 cells (2018)
  • Author(s): Yasuda K, Kitagawa Y, Kawakami R, Isaka Y, Watanabe H, Kondoh G, Kohwi-Shigematsu T, Sakaguchi S, Hirota K
  • Organizer: 6th Annual Meeting of the International Cytokine & Interferon Society
  • Int'l Joint Research
• [Presentation] Epigenetic landscape of FOXP3 enhancer sites during thymic FOXP3+ TREG development of CNS0- and CNS3-deficient mice (2018)
  • Author(s): Kawakami R, Kitagawa Y, Hirota K, Watanabe H, Kondoh G, Ohkura N, Sakaguchi S
  • Organizer: 6th Annual Meeting of the International Cytokine & Interferon Society
  • Int'l Joint Research
• [Presentation] GM-CSF-producing synovial ILCs exacerbate Th17-mediated autoimmune arthritis (2018)
  • Author(s): Hirota K, Hashimoto M, Ito Y, Matsuura M, Ito H, Tanaka M, Watanabe H, Kondoh G, Tanaka A, Yasuda K, Kopf M, Potocnik AJ, Stockinger B, Sakaguchi N, Sakaguchi S
  • Organizer: The 3rd International Conference on Innate Lymphoid Cells
  • Int'l Joint Research
• [Presentation] Autoimmune Th17 cells instruct ILC secretion of inflammatory GM-CSF to initiate and augment autoimmune arthritis (2018)
  • Author(s): Keiji Hirota
  • Organizer: 第47回 日本免疫学会学術集会
  • Int'l Joint Research / Invited
• [Presentation] Satb1-mediated regulation of GM-CSF and PD-1 in effector Th17 cells in experimental autoimmune encephalomyelitis (2018)
  • Author(s): Yasuda K, Kitagawa Y, Kawakami R, Watanabe H, Kondoh G, Kohwi-Shigematsu T, Sakaguchi S, Hirota K
  • Organizer: 第47回 日本免疫学会学術集会
  • Int'l Joint Research
• [Presentation] A role of Ripk3 and Gsdmd in the development of autoimmune arthritis in SKG mice (2018)
  • Author(s): Takeuchi Y, Watanabe H, Kondoh G, Sakaguchi N, Sakaguchi S, Mimori T, Hirota K
  • Organizer: 第47回 日本免疫学会学術集会
  • Int'l Joint Research
• [Presentation] An inflammatory cellular network of autoimmune Th17 cells, GM-CSF-producing ILCs and synoviocytes in the development of autoimmune arthritis (2017)
  • Author(s): Keiji Hirota
  • Organizer: Keystone symposia, Immune Regulation in Autoimmunity and Cancer
  • Place of Presentation: Whistler, Canada
  • Year and Date: 2017-03-26
  • Int'l Joint Research / Invited
• [Presentation] Satb1 controls the differentiation and terminal effector function of Th17 cells (2017)
  • Author(s): Keiko Yasuda, Yohko Kitagawa, Shimon Sakaguchi, Keiji Hirota
  • Organizer: 第46回 日本免疫学会学術集会
• [Presentation] Characterization of Innate lymphoid cells in gingiva of mice infected with Porphyromonas gingivalis (2017)
  • Author(s): Ryoki Kobayashi, Yohei Watanabe, Noriko M Tsuji, Keiji Hirota, Tomoko Kurita-Ochiai
  • Organizer: 第46回 日本免疫学会学術集会
• [Presentation] Inflammatory circuit of Th17 cells, GM-CSF-producing fibroblast-like synoviocytes, and ILCs in the development of autoimmune arthritis (2016)
  • Author(s): Keiji Hirota
  • Organizer: 第16回 国際免疫学会
  • Place of Presentation: Melbourne, Australia
  • Year and Date: 2016-08-21
  • Int'l Joint Research