Cellular mechanisms that controls memory T cells activation in the bone marrow during secondary immune responses.

• Project/Area Number: 19K21331
• Project/Area Number (Other): 18H06232 (2018)
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund (2019); Single-year Grants (2018)
• Review Section: 0904:Internal medicine of the bio-information integration and related fields
• Research Institution: Kyoto University
• Principal Investigator: Takeshi Ito 京都大学, iPS細胞研究所, 特定拠点助教 (60825941)
• Project Period (FY): 2018-08-24 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 骨髄 / 血管内皮細胞 / 記憶T細胞 / 抗原提示 / 骨髄血管内皮細胞 / 二次免疫応答

Outline of Research at the Start

骨髄には、記憶T細胞が長期間維持されている事が知られているが、脾臓やリンパ節といった二次リンパ組織とは組織学的構造や構成する細胞の種類が異なる骨髄において、記憶T細胞がどのように活性化するかは明らかになっていない。骨髄における記憶CD8+T細胞の活性化機構を明らかにするために、骨髄中での抗原の分布および記憶CD8+T細胞が活性化する際の動態（抗原提示細胞との位置関係、移動速度、サイトカイン産生）をFACS解析や生体イメージング法を用いて詳細に解析する。

Outline of Final Research Achievements

Memory T cells are maintained in the bone marrow after infection of pathogenic organisms and vaccination. The memory T cells are crucial for efficient secondary immune responses during re-infection of the same pathogens. The bone marrow is widely known as a major hematopoietic organ, and how memory T cells in the bone marrow are activated is not fully understood. In this study, we found that bone marrow endothelial cells have a capacity to incorporate exogenous soluble antigens and cross-present them to memory CD8+ T cells in the bone marrow. In the future, we will clarify biological significance of the antigen cross-presentation capacity in bone marrow endothelial cells.

Academic Significance and Societal Importance of the Research Achievements

本研究では、これまで十分には知られていなかった骨髄における記憶T細胞の活性化機構を、骨髄血管内皮細胞の抗原提示能の発見により明らかにしたものである。本研究が貢献した骨髄における抗原特異的免疫応答機構の解明は、免疫異常が原因とされる造血器疾患（再生不良性貧血・特発性血小板減少性紫斑病）の病態解明に寄与したり、造血器悪性腫瘍に対する免疫療法（CAR-T細胞療法、免疫チェックポイント阻害薬）の効果の増強に寄与するものである。

Research Products

• [Journal Article] Selective expression of claudin-5 in thymic endothelial cells regulates the blood-thymus barrier and T-cell export (2021)
  • Author(s): Takahiro Nagatake, Yan-Chun Zhao, Takeshi Ito, Masahiko Itoh, Kohei Kometani, Mikio Furuse, Azusa Saika, Eri Node, Jun Kunisawa, Nagahiro Minato, Yoko Hamazaki
  • Journal Title: International Immunology Volume: 33(3) Issue: 3 Pages: 171-182
  • DOI: 10.1093/intimm/dxaa069
  • Peer Reviewed / Open Access
• [Journal Article] Bone Marrow Endothelial Cells Take Up Blood-Borne Immune Complexes via Fcγ Receptor IIb2 in an Erythropoietin-Dependent Manner (2020)
  • Author(s): Ito Takeshi、Kometani Kohei、Minato Nagahiro、Hamazaki Yoko
  • Journal Title: The Journal of Immunology Volume: 205 Issue: 8 Pages: 2008-2015
  • DOI: 10.4049/jimmunol.1901101
  • Peer Reviewed
• [Presentation] 骨髄血管内皮細胞は交差抗原提示により記憶CD8+T細胞を迅速かつ持続的に活性化する (2020)
  • Author(s): 伊藤健、湊長博、濱崎洋子
  • Organizer: 第７２回日本細胞生物学会大会
• [Presentation] Bone marrow endothelial cells induce rapid activation and persistent proliferation of memory CD8+ T cells by cross-presentation of blood-borne antigens (2020)
  • Author(s): Takeshi Ito, Nagahiro Minato, and Yoko Hamazaki
  • Organizer: Keystone Symposia Conference Stromal Cells in Immunity and Disease
  • Int'l Joint Research
• [Presentation] Bone marrow endothelial cells induce rapid activation of memory CD8+ T cells by cross-presentation of blood-borne antigens. (2019)
  • Author(s): Takeshi Ito, Nagahiro Minato, and Yoko Hamazaki
  • Organizer: 第４８回日本免疫学会学術集会
• [Remarks] エリスロポエチンが骨髄の血管内皮細胞による免疫複合体の除去を促進する
  • URL: https://www.cira.kyoto-u.ac.jp/j/research/finding/200916-100000.html