Nature系列综述：西湖大学董晨院士系统总结CD8⁺T耗竭的调控因子

Core Viewpoint - T cell exhaustion is a unique state of T cell dysfunction that occurs during chronic antigen stimulation, significantly impacting immune responses in chronic infections and cancer [5][6]. Group 1: Mechanisms of T Cell Exhaustion - T cell exhaustion is characterized by impaired effector functions, reduced proliferation, and sustained expression of inhibitory receptors such as PD1, LAG3, and TIM3 [5]. - The development of T cell exhaustion is coordinated by complex interactions among transcriptional, epigenetic, and environmental factors, with transcription factors like NFAT, TOX, and NR4A1 playing crucial roles [5][12]. - Recent studies have identified a unique cell population known as exhausted T cell precursors (Tpex), which retain proliferative capacity and respond to immune checkpoint blockade therapy, providing insights for potential therapeutic strategies [5][6]. Group 2: Environmental Regulation of T Cell Exhaustion - The microenvironment significantly influences CD8⁺ T cell exhaustion, with various cytokines and metabolites modulating T cell function and fate [10][14]. - Understanding the environmental signals that drive or limit T cell exhaustion is essential for rejuvenating T cell responses in chronic diseases and enhancing the effectiveness of immunotherapy [6][14]. Group 3: Therapeutic Implications - The review highlights the importance of understanding the regulatory factors of T cell exhaustion to develop and improve immunotherapies targeting these pathways for cancer and chronic infections [14]. - By elucidating the mechanisms that guide the fate and function of different exhausted T cell subsets, the research provides critical references for developing targeted immunotherapies [14].