Sharma Piyush, Guo Ao, Poudel Suresh, Boada-Romero Emilio, Verbist Katherine C, Palacios Gustavo, Immadisetty Kalyan, Chen Mark J, Haydar Dalia, Mishra Ashutosh, Peng Junmin, Babu M Madan, Krenciute Giedre, Glazer Evan S, Green Douglas R
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Oncology, National Key Laboratory of Immune Response and Immunotherapy, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Nat Immunol. 2025 Jul 23. doi: 10.1038/s41590-025-02223-6.
T cell receptor (TCR) activation is regulated in many ways, including niche-specific nutrient availability. Here we investigated how methionine (Met) availability and TCR signaling interplay during the earliest events of T cell activation affect subsequent cell fate. Limiting Met during the initial 30 min of TCR engagement increased Ca influx, NFAT1 (encoded by Nfatc2) activation and promoter occupancy, leading to T cell exhaustion. We identified changes in the protein arginine methylome during initial TCR engagement and identified an arginine methylation of the Ca-activated potassium transporter KCa3.1, which regulates Ca-mediated NFAT1 signaling for optimal activation. Ablation of KCa3.1 arginine methylation increased NFAT1 nuclear localization, rendering T cells dysfunctional in mouse tumor and infection models. Furthermore, acute, early Met supplementation reduced nuclear NFAT1 in tumor-infiltrating T cells and augmented antitumor activity. These findings identify a metabolic event early after T cell activation that affects cell fate.
T细胞受体（TCR）激活受到多种方式的调控，包括特定微环境中的营养物质可用性。在此，我们研究了在T细胞激活的最早阶段，蛋氨酸（Met）可用性与TCR信号传导之间的相互作用如何影响后续细胞命运。在TCR参与的最初30分钟内限制Met会增加Ca内流、NFAT1（由Nfatc2编码）激活及启动子占据，导致T细胞耗竭。我们确定了初始TCR参与过程中蛋白质精氨酸甲基化组的变化，并鉴定出钙激活钾转运体KCa3.1的精氨酸甲基化，其调节钙介导的NFAT1信号以实现最佳激活。KCa3.1精氨酸甲基化的缺失增加了NFAT1的核定位，使T细胞在小鼠肿瘤和感染模型中功能失调。此外，急性早期补充Met可减少肿瘤浸润T细胞中的核NFAT1并增强抗肿瘤活性。这些发现确定了T细胞激活后早期影响细胞命运的代谢事件。
