Spatiotemporal regulation of NKT cell production by Rap1 GTPase

• Project/Area Number: 20K07554
• 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: Kansai Medical University
• Principal Investigator: UEDA Yoshihiro 関西医科大学, 医学部, 講師 (90533208)
• 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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: Rap1 / 胸腺 / NKT / インテグリン / 細胞極性 / NKT細胞

Outline of Research at the Start

NKT細胞は多くの人間で共通のT細胞受容体によりCD1dに提示された脂質を認識する自然T細胞で脾臓・肝臓・肺や腸組織に常在して、組織の炎症反応やがん免疫を制御していると考えられている。本研究では、NKT細胞の分化および活性化におけるリンパ球の接着と移動を調節する分子Rap1の欠損の影響を検討することで、Rap1によるNKT細胞の分化や活性化における接着・動態制御ポイントが明らかする。これにより、NKT細胞応答を制御する炎症やがんの新規の分子標的薬の開発が期待される。このようなNKTを標的とした治療薬は、TCR多様性が少なく多くの患者で共通である利点があり、効率性かつ有用性が期待される。

Outline of Final Research Achievements

Invariant NKT cells are a special subset of t cells to recognize fatty antigen and essential role for tumor immunity. In this study, We investigate the role of small GTPase Rap1 in NKT cell production and activation. By using knockout animal model, we found that Rap1 deficiency reduced NKT cells without TCR repertoire alternation in the thymus. Rap1 deficiency also required for activation of the periphery in response to alpha-Galactosylceramide. These data indicate Rap1 is required for NKT cell production and activation.

Academic Significance and Societal Importance of the Research Achievements

NKT細胞は多くの人間で共通のT細胞受容体によりCD1dに提示された脂質を認識する自然T細胞で脾臓・肝臓・肺や腸組織に常在して、組織の炎症反応やがん免疫を制御していると考えられている。本研究により、接着動態シグナル分子であるRap1が胸腺におけるNKT細胞の分化や末梢における活性化を調節することが明らかになった。これにより、NKT細胞応答を制御する炎症やがんの新規の分子標的薬の開発が期待される。このようなNKTを標的とした治療薬は、TCR多様性が少なく多くの患者で共通である利点があり、効率性かつ有用性が期待される。

Research Products

• [Journal Article] LFA1 Activation: Insights from a Single-Molecule Approach (2022)
  • Author(s): Kondo Naoyuki、Ueda Yoshihiro、Kinashi Tatsuo
  • Journal Title: Cells Volume: 11 Issue: 11 Pages: 1751-1751
  • DOI: 10.3390/cells11111751
  • Peer Reviewed / Open Access
• [Journal Article] Kindlin-3 disrupts an intersubunit association in the integrin LFA1 to trigger positive feedback activation by Rap1 and talin1, (2021)
  • Author(s): Kondo N, Ueda Y, Kinashi T.
  • Journal Title: Sci Signal. Volume: Vol 14, Issue 686. Issue: 686
  • DOI: 10.1126/scisignal.abf2184
  • Peer Reviewed
• [Journal Article] MST1/2 Balance Immune Activation and Tolerance by Orchestrating Adhesion, Transcription, and Organelle Dynamics in Lymphocytes (2020)
  • Author(s): Ueda Yoshihiro、Kondo Naoyuki、Kinashi Tatsuo
  • Journal Title: Frontiers in Immunology Volume: 11 Pages: 733-733
  • DOI: 10.3389/fimmu.2020.00733
  • Peer Reviewed / Open Access
• [Presentation] Rap1 facilitates cell polarization via RhoA signaling in T cells (2022)
  • Author(s): Y. Ueda, K. Higasa, Y. Kamioka, N. Kondo, S. Horitani, Y. Ikeda, T. Fukuhara, Y. Fukui, T. Kinashi
  • Organizer: The 51st Annual Meeting of the Japanese Society for Immunology, 2022.12, Kumamoto
  • Int'l Joint Research
• [Presentation] Distinct binding properties of integrin adaptors talin1 and kindlin-3 to LFA1 and α4 integrins modulate adhesive responses in static and shear-flow (2022)
  • Author(s): N. Kondo, Y. Kamioka, Y. Ikeda, Y. Ueda, T. Kinashi
  • Organizer: The 51st Annual Meeting of the Japanese Society for Immunology, 2022.12, Kumamoto
  • Int'l Joint Research
• [Presentation] Subsecond Rap1 activation by outside-in signaling of LFA1/ICAM1 interactions strengthens L-selectin mediated rolling of T cells (2022)
  • Author(s): Y. Kamioka, Y. Ueda, N. Kondo, Y. Ikeda, T. Kinashi
  • Organizer: The 51st Annual Meeting of the Japanese Society for Immunology, 2022.12, Kumamoto
  • Int'l Joint Research
• [Presentation] The critical role of Rap1GAPs in T cell recirculation and egress from lymph node. (WS01-18-P) (2022)
  • Author(s): S. Horitani, Y. Ueda, Y. Kamioka, N. Kondo, Y. Ikeda T. Fukuhara, M. Naganuma, T. Kinashi
  • Organizer: The 51st Annual Meeting of the Japanese Society for Immunology, 2022.12, Kumamoto
  • Int'l Joint Research
• [Presentation] Rap1 facilitates T cell polarity via spatial regulation of MLC and ARAP1 (2021)
  • Author(s): Yoshihiro Ueda, Koichiro Higasa, Yuji Kamioka, Naoyuki Kondo, Tatsuo Kinashi
  • Organizer: The 50th Annual Meeting of the Japanese Society for Immunology
• [Presentation] Differential requirement of Rap1 and integrin adaptors for distinct modalities of T cell adhesion under shear flow (2021)
  • Author(s): Yuji Kamioka, Yoshihiro Ueda, Naoyuki Kondo, Tatsuo Kinashi
  • Organizer: The 50th Annual Meeting of the Japanese Society for Immunology
• [Presentation] Kindlin-3 breaks of integrin LFA-1 inhibitory clasp to promote positive feedback activation of LFA-1 by talin1 and Rap1 (2021)
  • Author(s): Naoyuki Kondo, Yoshihiro Ueda, Tatsuo Kinashi
  • Organizer: The 50th Annual Meeting of the Japanese Society for Immunology
• [Presentation] Rap1/Talin-1/Kindlin-3を内包する新規ポジティブフィードバック回路によるインテグリン活性化の離散的制御 (2020)
  • Author(s): 近藤直幸、植田祥啓、木梨達雄
  • Organizer: 第43回日本分子生物学会年会 、2P-0195
• [Book] 食品免疫学事典 (2021)
  • Author(s): 日本食品免疫学会
  • Total Pages: 492
  • Publisher: 朝倉書店
  • ISBN: 9784254431261