TNF受容体型補助刺激分子による自然リンパ球の制御機構

2022 Fiscal Year Annual Research Report

• Project/Area Number: 20K07546
• Research Institution: Tohoku University
• Principal Investigator: 奥山 祐子 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
• Keywords: ２型自然リンパ球 / 補助刺激分子 / アレルギー疾患 / GITR

Outline of Annual Research Achievements

自然リンパ球（ILC）は、自然免疫系を担う新たなリンパ球系細胞として発見され、炎症反応を制御し生体恒常性維持と生体防御に重要な細胞として注目されている。なかでも２型自然リンパ球（ILC2）は、Th2サイトカインの産生を介してアレルギー性呼吸器炎症、寄生虫感染防御、アトピー性皮膚炎等の病態形成に関与する。
我々はTNF受容体型のT細胞補助刺激分子の一つであるGITR (Glucocorticoid induced tumor necrosisfactor receptor)がILC2に強く発現することを見いだした。そして、GITRシグナルが肺組織ILC2の増殖と活性化を促進し、アレルギー性肺炎症疾患の発症に寄与することを明らかにした。さらに、GITRリガンド(GITRL)発現細胞の探索を進めたところ、炎症時ILC2自身にリガンドの発現が誘導されることを見出した。ILC2細胞上のGITR-LはILC2同士の相互作用による制御、およびT細胞に発現するGITRを介したT細胞の機能制御にも関与すると考えられる。そこで本研究は、ILCにおけるGITR補助刺激シグナルを介したアレルギー性炎症疾患の制御機構を明らかにすることを目的とする。
これまでの研究の結果、マウス由来ILC2についてIL-33刺激による活性化後、およびパパインによる炎症誘導後にGITR-Lの発現の亢進が認められ、GITR-L欠損マウスではILC2依存的な肺炎症病態が減弱した。また、ヒト末梢血由来ILC2を培養しin vitroにおいてサイトカイン刺激を行なったところ、活性化による補助刺激分子発現の変化が認められた。さらに、in vitro ILC2において各補助刺激シグナルの機能評価を行った。

Research Products

• [Journal Article] L-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] 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: Biol Pharm Bull. Volume: 45(12) Pages: 1798-1804
  • DOI: 10.1248/bpb.b22-00493.
  • Peer Reviewed
• [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