Rapid metabolic regulation of a novel arginine methylation of KCa3.1 attenuates T cell exhaustion

ABSTRACT T cell receptor (TCR) engagement initiates the activation process, and this signaling event is regulated in multifaceted ways. Nutrient availability in the immediate niche is one such mode of regulation 1–3 . Here, we investigated how the availability of an essential amino acid methionine (Met) and TCR signaling might interplay in the earliest events of T cell activation to affect subsequent T cell fate and function. We found that limiting Met during only the initial 30 minutes of CD8 + T cell activation increased Ca 2+ influx, Ca 2+ -mediated NFAT1 ( Nfatc2 ) activation, NFAT1 promoter occupancy, and T cell exhaustion. We identified changes in the protein arginine methylome during the initial 30 min of TCR engagement and discovered a novel arginine methylation of a Ca 2+ -activated potassium transporter, KCa3.1, which regulates Ca 2+ -mediated NFAT1 signaling to ensure optimal activation. Ablation of arginine methylation in KCa3.1 led to increased NFAT1 activation, 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 the subsequent fate of the cell.