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

T cell exhaustion is linked to persistent antigen exposure and perturbed activation events, correlating with poor disease prognosis. Tumor-mediated T cell exhaustion is well documented; however, how the nutrient-deprived tumor niche affects T cell receptor (TCR) activation is largely unclear. We show that methionine metabolism licenses optimal TCR signaling by regulating the protein arginine methylome, and limiting methionine availability during early TCR signaling promotes subsequent T cell exhaustion. We discovered a novel arginine methylation of a Ca2+-activated potassium transporter, KCa3.1, prevention of which results in increased Ca2+-mediated NFAT1 activation, NFAT1 promoter occupancy, and T cell exhaustion. Furthermore, methionine supplementation reduces nuclear NFAT1 in tumor-infiltrating T cells and augments their anti-tumor activity. These findings demonstrate metabolic regulation of T cell exhaustion determined during TCR engagement. ### Competing Interest Statement D.R.G. consulted for Venus Therapeutics, Boehringer-Ingelheim and Asha Pharmaceuticals. E.S.G consulted for Anviron. G.K. has patent applications in field of cell or gene therapy in cancer and has received honoraria from Cell Signaling and Kineticos.