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<p>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<sup>2+</sup> influx, NFAT1 (encoded by <i>Nfatc2</i>) 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<sup>2+</sup>-activated potassium transporter KCa3.1, which regulates Ca<sup>2+</sup>-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.</p>

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Early methionine availability attenuates T cell exhaustion

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月23日

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  • Piyush Sharma,
  • Ao Guo,
  • Suresh Poudel,
  • Emilio Boada-Romero,
  • Katherine C. Verbist,
  • Gustavo Palacios,
  • Kalyan Immadisetty,
  • Mark J. Chen,
  • Dalia Haydar,
  • Ashutosh Mishra,
  • Junmin Peng,
  • M. Madan Babu,
  • Giedre Krenciute,
  • Evan S. Glazer,
  • Douglas R. Green

摘要

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 Ca2+ 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 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 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.