Elucidation of NK cell activation and retrovirus infection defense mechanism induced by peptide immunization against murine Friend retrovirus

• Project/Area Number: 19K16622
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Kindai University
• Principal Investigator: KATO Shigeki 近畿大学, 医学部, 助教 (90790767)
• Project Period (FY): 2019-04-01 – 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: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: レトロウイルス / ワクチン / がん / 転移 / NK 細胞 / NK cell / 白血病 / HIV

Outline of Research at the Start

HIV 感染に対する有効な予防ワクチンは，長年の研究資源投入にもかかわらず現在でも確立しておらず，感染ごく初期の免疫応答，特に感染細胞に対する NK 細胞の機能解析が，HIV をはじめとするレトロウイルス感染予防に極めて重要な因子として精力的に研究が進められている．
本研究では，これまで申請者の研究グループが世界をリードしてきたマウスフレンドレトロウイルス感染モデルを活用し，感染防御性免疫が積極的に NK 細胞活性化と感染細胞の NK 細胞に対する高い感受性を誘導することで感染細胞が効率的に排除されることを証明し，新たな抗レトロウイルスワクチン戦略を提示する．

Outline of Final Research Achievements

We worked on elucidating the host immune response, especially the activation mechanism of NK cells, using a mouse retrovirus and an infection-defensive mouse model. Early activation of NK cells is required for elimination of infected cells, but the specific effector mechanism was unknown. We found in this study that IL-21 expression by antigen-specific follicular helper T cells in the early stage of infection acts on IL-21 R on NK cells to induce maturation and activation of NK cells, which clearly eliminated the infected cells. Furthermore, it was revealed that CD154 on NK cells regulates IL-21 R expression by receiving stimuli from CD40 of dendritic cells and macrophages in the early stage of infection.

Academic Significance and Societal Importance of the Research Achievements

本研究は，適切なエピトープ選択による免疫によって早期に Tfh が誘導されることは，NK細胞の活性化をもたらすことにつながりウイルス感染細胞を効率的に排除することが可能であるという新規メカニズムを証明したことを意味し，新たなワクチン開発につながることが期待される．
従来，NK 細胞は抗原感作が不要と考えられてきたが，CD4 陽性 T 細胞を適切なエピトープで免疫すれば NK 細胞に間接的に抗原特異性を賦与できること，また，樹状細胞やマクロファージなどの抗原提示細胞の CD40 分子が効率的な NK 細胞活性化に重要であるという分子基盤を明らかにした．

Research Products

• [Journal Article] Optimization of the delivery of molecules into lymph nodes using a lymphatic drug delivery system with ultrasound (2021)
  • Author(s): Kato Shigeki、Yoshiba Shota、Mori Shiro、Kodama Tetsuya
  • Journal Title: International Journal of Pharmaceutics Volume: 597 Pages: 120324-120324
  • DOI: 10.1016/j.ijpharm.2021.120324
  • Peer Reviewed / Open Access
• [Journal Article] Intranodal pressure of a metastatic lymph node reflects the response to lymphatic drug delivery system (2020)
  • Author(s): Kato Shigeki、Takeda Kazu、Sukhbaatar Ariunbuyan、Sakamoto Maya、Mori Shiro、Shiga Kiyoto、Kodama Tetsuya
  • Journal Title: Cancer Science Volume: 111 Issue: 11 Pages: 4232-4241
  • DOI: 10.1111/cas.14640
  • Peer Reviewed / Open Access
• [Journal Article] In vivo delivery of an exogenous molecule into murine T lymphocytes using a lymphatic drug delivery system combined with sonoporation. (2020)
  • Author(s): Kato S, Shirai Y, Motozono C, Kanzaki H, Mori S, Kodama T
  • Journal Title: Biochem Biophys Res Commun Volume: - Issue: 4 Pages: 1025-1031
  • DOI: 10.1016/j.bbrc.2020.02.174
  • Peer Reviewed / Open Access
• [Journal Article] Use of a lymphatic drug delivery system and sonoporation to target malignant metastatic breast cancer cells proliferating in the marginal sinuses. (2019)
  • Author(s): Kato S, Shirai Y, Sakamoto M, Mori S, Kodama T
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 13242-13242
  • DOI: 10.1038/s41598-019-49386-5
  • Peer Reviewed / Open Access
• [Journal Article] Interstitial-resident memory CD8+ T cells sustain frontline epithelial memory in the lung. (2019)
  • Author(s): Takamura, S., Kato, S., Motozono, C., Shimaoka, T., Ueha, S., Matsuo, K., Miyauchi, K., Masumoto, T., Katsushima, A., Nakayama, T., Tomura, M., Matsushima, K., Kubo, M. & Miyazawa, M.
  • Journal Title: J Exp Med. Volume: 216 Issue: 12 Pages: 2736-2747
  • DOI: 10.1084/jem.20190557
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Fate determination with a selected epitope facilitates follicular helper cell differentiation and protection against acute retroviral infection (2020)
  • Author(s): Chihiro Motozono, Shigeki Kato, Sachiyo Kawahara, Shiki Takamura, Masaaki Miyazawa
  • Organizer: 21st Kumamoto AIDS Seminar
  • Int'l Joint Research