Critical role of plasmacytoid dendritic cells in induction of oral tolerance

• Project/Area Number: 18K15194
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: University of Miyazaki
• Principal Investigator: Takagi Hideaki 宮崎大学, 医学部, 助教 (10719628)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 形質細胞様樹状細胞 / 経口免疫寛容 / 粘膜免疫 / 制御性T細胞 / 抗原特異的 / アレルギー / 腸管免疫 / 抗原特異的Foxp3+Treg

Outline of Final Research Achievements

Exposure to dietary constituents through the mucosal surface of the gastrointestinal tract generates oral tolerance that prevents deleterious T cell-mediated immunity. While oral tolerance is an active process that involves the emergence of CD4+Foxp3+ regulatory T (Treg) cells in gut-associated lymphoid tissues (GALT) for the suppression of effector T (Teff) cells, how antigen (Ag)-presenting cells (APCs) initiate this process remains unclear. In this study, we sought to determine the role of plasmacytoid dendritic cells (pDCs), known as unconventional type APCs, in the establishment of oral tolerance. In conclusion, we report that gastrointestinal pDC-mediated tolerogenesis through de novo generation of CD4+Foxp3+ iTreg cells impacts the induction of oral tolerance leading to the abortive allergic responses.

Academic Significance and Societal Importance of the Research Achievements

本研究課題の意義として、これまで未知であった『腸管適応免疫応答の制御機構』に関する“pDC機能”の重要性が解明されることから新たな概念が提唱され、当該分野の発展に積極的に貢献できることが挙げられる。
さらに“pDC機能”に関する生物製剤などの分子標的創薬の研究開発が、ヒトpDCの生体内動態に基づいた腸管免疫疾患の病勢診断法とともに革新的な分子標的治療法の確立、ならびに感染症への新規経口粘膜ワクチンの開発を導くことが強く期待される。

Research Products

• [Journal Article] Essential role of submandibular lymph node dendritic cells in protective sublingual immunotherapy against murine allergy (2020)
  • Author(s): Miyanaga Noriaki、Takagi Hideaki、Uto Tomofumi、Fukaya Tomohiro、Nasu Junta、Fukui Takehito、Nishikawa Yotaro、Sparwasser Tim、Choijookhuu Narantsog、Hishikawa Yoshitaka、Nakamura Takeshi、Tono Tetsuya、Sato Katsuaki
  • Journal Title: Communications Biology Volume: 3 Issue: 1 Pages: 1-12
  • DOI: 10.1038/s42003-020-01466-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pivotal role of the carbohydrate recognition domain in self-interaction of CLEC4A to elicit the ITIM-mediated inhibitory function in murine conventional dendritic cells in vitro (2020)
  • Author(s): Nasu Junta、Uto Tomofumi、Fukaya Tomohiro、Takagi Hideaki、Fukui Takehito、Miyanaga Noriaki、Nishikawa Yotaro、Yamasaki Sho、Yamashita Yoshihiro、Sato Katsuaki
  • Journal Title: International Immunology Volume: 32 Issue: 10 Pages: 673-682
  • DOI: 10.1093/intimm/dxaa034
  • Peer Reviewed
• [Journal Article] Pivotal role of CD103 in the development of psoriasiform dermatitis (2020)
  • Author(s): Fukui Takehito、Fukaya Tomohiro、Uto Tomofumi、Takagi Hideaki、Nasu Junta、Miyanaga Noriaki、Nishikawa Yotaro、Koseki Haruhiko、Choijookhuu Narantsog、Hishikawa Yoshitaka、Yamashita Yoshihiro、Sato Katsuaki
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 1-11
  • DOI: 10.1038/s41598-020-65355-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The HDAC Inhibitor, SAHA, Combined with Cisplatin Synergistically Induces Apoptosis in Alpha-fetoprotein-producing Hepatoid Adenocarcinoma Cells (2019)
  • Author(s): Kyaw MTH, Yamaguchi Y, Choijookhuu N, Yano K, Takagi H, Takahashi N, Synn Oo P, Sato K, Hishikawa Y.
  • Journal Title: ACTA HISTOCHEMICA ET CYTOCHEMICA Volume: 52 Issue: 1 Pages: 1-8
  • DOI: 10.1267/ahc.18044
  • NAID: 130007605543
  • ISSN: 0044-5991, 1347-5800
  • Year and Date: 2019-02-28
  • Peer Reviewed / Open Access
• [Journal Article] Pivotal Role of IL-22 Binding Protein in the Epithelial Autoregulation of Interleukin-22 Signaling in the Control of Skin Inflammation (2018)
  • Author(s): Tomohiro Fukaya, Takehito Fukui, Tomofumi Uto, Hideaki Takagi, Junta Nasu, Noriaki, Miyanaga, Keiichi Arimura, Takeshi Nakamura, Haruhiko Koseki, Narantsog Choijookhuu, Yoshitaka Hishikawa, Katsuaki Sato
  • Journal Title: Frontiers in Immunology Volume: 9 Pages: 1-13
  • DOI: 10.3389/fimmu.2018.01418
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Essential role of submandibular lymph node conventional dendritic cells in the protective effect of sublingual immunotherapy on allergic asthma (2019)
  • Author(s): 高木秀明、宮永宜明、宇都倫史、深谷知宏、奈須遵太、福井丈仁、西川陽太郎、佐藤克明
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] Crucial role of conventional dendritic cells in the protective effect of sublingual immunotherapy (SLIT) on allergic disorders. (2018)
  • Author(s): 高木秀明、宮永宣明、宇都倫史、深谷知宏、奈須遵太、福井丈仁、佐藤克明
  • Organizer: 第46回日本免疫学会総会