Regulatory mechanism of innate lymphoid cells by TNFRSF co-stimulatory molecules

• Project/Area Number: 20K07546
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Tohoku University
• Principal Investigator: Okuyama Yuko 東北大学, 医学系研究科, 助教 (50624475)
• Co-Investigator(Kenkyū-buntansha): 河部 剛史 東北大学, 医学系研究科, 准教授 (50834652)
• 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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 自然リンパ球 / ILC2 / 補助刺激 / GITR / アレルギー / ２型自然リンパ球 / 補助刺激分子 / アレルギー疾患 / TNF受容体型T細胞補助刺激分子 / ILC / アレルギ性疾患

Outline of Research at the Start

本研究は補助刺激シグナルによるILC同士およびILC-T細胞間相互作用を介したアレルギー性炎症疾患の発症機序を明らかにすることを目的とする。マウスアレルギー性肺炎症モデルを用い細胞間相互作用を解明する。さらに、ヒトILCを用いた解析により、GITR-L/GITR補助刺激の治療・診断の標的としての有用性を検証し、アレルギー性炎症疾患の新規治療標法・診断法開発への応用を目指す。

Outline of Final Research Achievements

We have previously shown that GITR, a TNF receptor-type T cell co-stimulator, promotes proliferation and activation of lung tissue type 2 innate lymphocytes (ILC2) and contributes to the pathogenesis of allergic lung inflammatory disease. In this study, we found that GITR ligand (GITRL) expression is induced by ILC2 itself during inflammation, and ILC2-dependent lung inflammatory disease pathology was attenuated in GITR-L-deficient mice. In addition, the expression changes and functions of each co-stimulatory signal were confirmed in human peripheral blood-derived ILC2. These findings suggest that co-stimulatory signals on ILC2 cells may be involved in the regulation of ILC2 interactions as well as in the regulation of T cell function.

Academic Significance and Societal Importance of the Research Achievements

これまで補助刺激分子はT細胞に発現し、抗原依存的なT細胞の活性化を制御することが知られているが、抗原受容体を持たない自然リンパ球に発現する補助刺激分子はT細胞とは異なる新規の機能を有する。この機能の詳細を解析した点で本研究は学術的な意義が高い。またILC2はアレルギー疾患の発症に関与することから、GITR-GITRLシグナルを介したILC2の機能制御を明らかにすることで、これらを標的としたアレルギー疾患の新規治療法開発に繋がることから、社会的意義が大きい研究成果である。

Research Products

• [Journal Article] OX40 Ligand-Mannose-Binding Lectin Fusion Protein Induces Potent OX40 Cosignaling in CD4⁺ T Cells (2022)
  • Author(s): Sato A, Azuma M, Nagai H, Imai W, Kawaguchi K, Morita M, Okuyama Y, Ishii N, So T.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 45 Issue: 12 Pages: 1798-1804
  • DOI: 10.1248/bpb.b22-00493
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2022-12-01
  • Peer Reviewed
• [Journal Article] IL-33-ILC2 axis promotes anti-tumor CD8+ T cell responses via OX40 signaling (2022)
  • Author(s): Okuyama Y, Okajima A, Sakamoto N, Hashimoto A, Tanabe R, Kawajiri A, Kawabe T, Ishii N
  • Journal Title: Biochem Biophys Res Commun Volume: 637 Pages: 9-16
  • DOI: 10.1016/j.bbrc.2022.11.006
  • Peer Reviewed
• [Journal Article] TNF Receptor-Associated Factor 5 Limits IL-27 Receptor Signaling in CD4 + T Lymphocytes (2022)
  • Author(s): Kawahara E, Azuma M, Nagashima H, Omori K, Akiyama S, Fujimori Y, Oishi M, Shibui N, Kawaguchi K, Morita M, Okuyama Y, Ishii N, So T.
  • Journal Title: J Immunol. Volume: 208(3) Issue: 3 Pages: 642-650
  • DOI: 10.4049/jimmunol.2001358
  • Peer Reviewed
• [Journal Article] Phenotypic heterogeneity in individuals with MECOM variants in 2 families. (2022)
  • Author(s): Niihori T, Tanoshima R, Sasahara Y, Sato A, Irie M, Saito-Nanjo Y, Funayama R, Shirota M, Abe T, Okuyama Y, Ishii N, Nakayama K, Kure S, Imaizumi M, Aoki Y.
  • Journal Title: Blood Adv. Volume: - Issue: 18 Pages: 5257-5261
  • DOI: 10.1182/bloodadvances.2020003812
  • Peer Reviewed / Open Access
• [Journal Article] Dysregulation of Rnf 213 gene contributes to T cell response via antigen uptake, processing, and presentation (2021)
  • Author(s): Tashiro R, Niizuma K, Kasamatsu J, Okuyama Y, Rashad S, Kikuchi A, Fujimura M, Kure S, Ishii N, Tominaga T.
  • Journal Title: J Cell Physiol. Volume: 236(11) Issue: 11 Pages: 7554-7564
  • DOI: 10.1002/jcp.30396
  • Peer Reviewed
• [Journal Article] GITR controls intestinal inflammation by suppressing IL-15-dependent NK cell activity. (2020)
  • Author(s): Sakurai T, Okuyama Y, Kobayashi S, Phung HT, Asao A, Kawabe T, Ndhlovu LC, Riccardi C, Kudo H, Wada M, Nio M, So T, Ishii N.
  • Journal Title: FASEB J. Volume: 34(11) Issue: 11 Pages: 14820-14831
  • DOI: 10.1096/fj.202001675r
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Excess proliferation and activation of self-reactive memory-phenotype CD4+ T lymphocytes are tonically inhibited by regulatory T cells in steady state (2022)
  • Author(s): Jing Li, Ziying Yang, Akihisa Kawajiri, Kosuke Sato, Shunichi Tayama, Yuko Okuyama, Naoto Ishii, Takeshi Kawabe
  • Organizer: The 51st Annual Meeting of The Japanese Society for Immunology
• [Presentation] CARS2-dependent sulfur metabolism controls intestinal inflammation by suppressing CD4+ T cell proliferation (2022)
  • Author(s): Shunichi Tayama, Takeshi Kawabe, Kyoga Hiraide, Jing Li, Ziying Yang, Kosuke Sato, Akihisa Kawajiri, Yuko Okuyama, Naoto Ishii
  • Organizer: The 51st Annual Meeting of The Japanese Society for Immunology
• [Presentation] Mitochondrial cysteinyl-tRNA synthetase (CARS2)-dependent sulfur metabolism exacerbates experimental autoimmune encephalomyelitis in mice (2022)
  • Author(s): Kyoga Hiraide, Yuya Kitamura, Shunichi Tayama, Yuko Okuyama, Kosuke Sato, Hibiki Suzuki, Keita Koinuma, Takeshi Kawabe, Naoto Ishii
  • Organizer: The 51st Annual Meeting of The Japanese Society for Immunology
• [Presentation] Rapid accumulation of circulating memory-phenotype CD4+ T lymphocytes in the gut critically contributes to tissue injury driven by intestinal ischemia and reperfusion (2022)
  • Author(s): Kosuke Sato, Jing Li, Ziying Yang, Akihisa Kawajiri, Shunichi Tayama, Yuko Okuyama, Motoshi Wada, Naoto Ishii, Takeshi Kawabe
  • Organizer: The 51st Annual Meeting of The Japanese Society for Immunology
• [Presentation] Immunological Functions of Memory-Phenotype CD4+ T lymphocytes in Anti-Tumor Responses and Graft- versus-Host Disease (2022)
  • Author(s): Ziying Yang, Hideaki Watanabe, Jing Li, Akihisa Kawajiri, Kosuke Sato, Shunichi Tayama, Yuko Okuyama, Naoto Ishii, Takeshi Kawabe
  • Organizer: The 51st Annual Meeting of The Japanese Society for Immunology
• [Presentation] Regulation of OX40 co-signaling by OX40 ligand-mannose-binding lectin fusion protein (2022)
  • Author(s): Ayaka Sato, Takanori So, Mitsuki Azuma, Hodaka Nagai, Masashi Morita, Yuko Okuyama, Naoto Ishii.
  • Organizer: The 51st Annual Meeting of The Japanese Society for Immunology
• [Presentation] ILC2-derived OX40L-OX40 signal promotes cytotoxic CD8+ T cell-mediated antitumor immunity in murine melanoma (2022)
  • Author(s): Yuko Okuyama, Akira Okajima, Nao Sakamoto, Ryuto Tanabe, Ayaka Hashimoto, Atsuko Asao, Ziying Yang, Akihisa Kawajiri, Takeshi Kawabe, Naoto Ishii.
  • Organizer: The 51st Annual Meeting of The Japanese Society for Immunology
• [Presentation] Self-reactive memory-phenotype CD4+ T lymphocytes can induce mild and systemic inflammation by differentiating into effector and regulatory T cells (2022)
  • Author(s): Akihisa Kawajiri, Jing Li, Ziying Yang, Keita Koinuma, Kosuke Sato, Shunichi Tayama, Yuko Okuyama, Hideo Harigae, Naoto Ishii, Jinfang Zhu, Kwang Soon Kim, Takeshi Kawabe.
  • Organizer: The 51st Annual Meeting of The Japanese Society for Immunology
• [Presentation] Characterization and composition of innate lymphoid cells in pediatric and adult allergic patients (2021)
  • Author(s): Yuko Okuyama, Tomomi Musha, Mizuna Fujita, Takeshi Kawabe, Atsuko Asao, Rina Morishita, Toshiya Takahashi, Maki Ozawa, Kenshi Yamasaki, Yohei Watanabe, Satoshi Horino, Yuji Saita, Yuji Nagano, Masaki Abe, Setsuya Aiba, Katsushi Miura, Naoto Ishii.
  • Organizer: The 50th Annual Meeting of the Japanese Society for Immunology
• [Presentation] TNF receptor-associated factor 5 reciprocally controls signals through IL-27 receptor and GITR in CD4+ T-lymphocytes (2021)
  • Author(s): Mitsuki Azuma, Masashi Morita, Yuko Okuyama, Naoto Ishii, Takanori So
  • Organizer: The 50th Annual Meeting of the Japanese Society for Immunology
• [Presentation] Inflammatory potential of self-driven memory-phenotype CD4+ T cells (2021)
  • Author(s): Akihisa Kawajiri, Minami Ishii, Li Jing, Yang Ziying, Kosuke Sato, Shunichi Tayama, Yuko Okuyama, Hideo Harigae, Naoto Ishii, Takeshi Kawabe
  • Organizer: The 50th Annual Meeting of the Japanese Society for Immunology
• [Presentation] Reactive sulfide species generated by cysteinyl-tRNA synthetase plays a regulatory role in T cell-induced colitis in a T cell-intrinsic manner (2021)
  • Author(s): Shunichi Tayama, Takeshi Kawabe, Yuya Kitamura, Kyoga Hiraide, Jing Li, Ziying Yang, Akihisa Kawajiri, Kosuke Sato, Yuko Okuyama, Masanobu Morita, Takaaki Akaike, Naoto Ishii
  • Organizer: The 50th Annual Meeting of the Japanese Society for Immunology