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

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. 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 Ca2+ influx, Ca2+-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 Ca2+-activated potassium transporter, KCa3.1, which regulates Ca2+-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.