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Early methionine availability attenuates T cell exhaustion

ABSTRACT: T cell receptor (TCR) activation is regulated in multifaceted ways, including niche-specific nutrient availability. We investigated how methionine (Met) availability and TCR signaling interplay in the earliest events of T cell activation to affect subsequent cell fate. Limiting Met during the initial 30 minutes of TCR engagement increased Ca2+ influx, NFAT1 (Nfatc2) activation and promoter occupancy leading to T cell exhaustion. We identified changes in the protein arginine methylome during the initial TCR engagement and discovered a novel arginine methylation of a 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 murine tumour and infection models. Furthermore, acute Met supplementation at early stages reduced nuclear NFAT1 in tumour-infiltrating T cells and augmented their anti-tumour activity. Our findings identify a metabolic event occurring early after T cell activation that influences cell fate.

ORGANISM(S): Mus musculus

PROVIDER: GSE221350 | GEO | 2025/05/29

REPOSITORIES: GEO

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An early, novel arginine methylation of KCa3.1 attenuates subsequent T cell exhaustion.

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