Cell function, receptor editing to develop a T-cell cytoskeleton-based biomicromachine.

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K16301
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kyoto University
• Principal Investigator: Minagawa Atsutaka 京都大学, iPS細胞研究所, 特定研究員 (90838822)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 人工受容体 / トロゴサイトーシス / シェディング / エンドサイトーシス

Outline of Final Research Achievements

In the process of creating artificial receptors with novel structures and evaluating their functions, it was discovered that the duration of signal transduction is prolonged and the function is enhanced when the receptors are structured in such a way that shedding, a phenomenon in which the extracellular domain of the receptor is cleaved, occurs. This phenomenon is due to the fact that shedding suppresses trogocytosis, a membrane protein exchange phenomenon between neighbouring cells, and maintains the expression level of the target protein on the target cell, as shown by inhibitors and mutagenesis that suppress shedding. They also found that the structure and size of the intracellular domain of the artificial receptor is closely related to the regulation of shedding and trogocytosis. This finding is considered to be a fundamental principle for future artificial receptor design.

Free Research Field

腫瘍免疫学

Academic Significance and Societal Importance of the Research Achievements

本研究の成果から、受容体シェディングによるトロゴサイトーシスの調整法についての基盤理論の構築に成功した。またシェディング構造を導入し、トロゴサイトーシスが抑制されたキメラ受容体は、動物実験にて増強された抗腫瘍効果を持つことを示すことに成功した。この結果はがん治療におけるキメラ受容体の新しい設計概念となるのみならず、シェディングとトロゴサイトーシスの関連は、すべての膜蛋白受容体にて起こっている現象であることが予想され、近接細胞間コミュニケーションを理解する上で重要な知見である。