Elucidation of the molecular mechanism of memory T cell exhaustion and development of its reprogramming method

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K19444
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: Keio University
• Principal Investigator: Yoshimura Akihiko 慶應義塾大学, 医学部(信濃町), 教授 (90182815)
• Project Period (FY): 2022-06-30 – 2024-03-31
• Keywords: 腫瘍免疫 / T細胞 / 免疫記憶 / 疲弊 / 転写因子 / CAR-T

Outline of Final Research Achievements

Memory T cells play a central role in tumor immunity, but in the tumor environment T cells become exhausted and fail to exert sufficient antitumor effects. We have identified the NR4a family of transcription factors that play a central role in T cell exhaustion. In this study, we used genetically engineered mice and single-cell RNA sequencing to examine how NR4a affects T cell memory differentiation and whether deletion of NR4a can unexhaust T cells and reprogram them to young memory T cells. The results showed that NR4a deficiency not only suppresses exhaustion but also converts T cells to young memory cells.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

これまで不明であったT細胞疲弊の分子機構の一端がNR4aを中心に初めて明らかにされた。さらにNR4aを阻害することで疲弊を解除するだけでなく、若いメモリーT細胞に転換できることを示たことは、T細胞分化の基礎研究のみならず、NR4aが抗腫瘍免疫の強力な標的分子になりうることを示せた意義は大きい。