圣犹达儿童研究医院Green, Douglas R.研究小组宣布他们开发出早期蛋氨酸可用性降低T细胞耗竭。这一研究成果于2025年7月23日发表在国际顶尖学术期刊《自然—免疫学》上。

在这里，该研究组研究了蛋氨酸（Met）有效性和TCR信号如何在T细胞活化影响随后的细胞命运。在最初的30年TCR参与增加Ca²⁺内流，NFAT1（由Nfatc2编码）激活和启动子占用，导致T细胞耗竭。课题组发现了在初始TCR参与过程中蛋白精氨酸甲基组的变化，并发现了Ca²⁺激活的钾转运蛋白KCa3.1的精氨酸甲基化，KCa3.1调节Ca²⁺介导的NFAT1信号的最佳激活。KCa3.1精氨酸甲基化的消融增加了NFAT1的核定位，使T无主题肿瘤和感染模型中的细胞功能障碍。

此外，急性、早期补充Met可降低肿瘤浸润性T细胞和增强抗肿瘤活性。这些发现确定了T影响细胞命运的细胞活化。

据介绍，T 细胞受体（TCR）的激活受到多种方式的调节，包括特定生态位的营养可利用性。

附：英文原文

Title: Early methionine availability attenuates Tcell exhaustion

Author: 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.

Issue&Volume: 2025-07-23

Abstract: Tcell 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 Tcell activation affect subsequent cell fate. Limiting Met during the initial 30min of TCR engagement increased Ca2+ influx, NFAT1 (encoded by Nfatc2) activation and promoter occupancy, leading to Tcell exhaustion. We identified changes in the protein arginine methylome during initial TCR engagement and identified an arginine methylation of the Ca2+-activated potassium transporter KCa3.1, which regulates Ca2+-mediated NFAT1 signaling for optimal activation. Ablation of KCa3.1 arginine methylation increased NFAT1 nuclear localization, rendering Tcells dysfunctional in mouse tumor and infection models. Furthermore, acute, early Met supplementation reduced nuclear NFAT1 in tumor-infiltrating Tcells and augmented antitumor activity. These findings identify a metabolic event early after Tcell activation that affects cell fate.

DOI: 10.1038/s41590-025-02223-6

Source: https://www.nature.com/articles/s41590-025-02223-6