Rapid metabolic regulation of a novel arginine methylation of KCa3.1 attenuates 1 T cell exhaustion 2257

Abstract Description T cell mediated anti-tumour immunity depends on optimal T cell activation. 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. Methionine (Met) is among the amino acids depleted in the tumour microenvironment (TME), and its supplementation has been shown to enhance anti-tumour immunity. Here, we investigated how Met availability and TCR signaling might interplay in the earliest events of T cell activation to affect T cell fate and function. We found that limiting Met to levels found in the TME during only the initial 30 minutes of CD8+ T cell activation increased Ca2+ influx and compromised the subsequent anti-tumour immunity of T cells transferred into tumour-bearing mice. We identified changes in the protein arginine methylome during TCR engagement and discovered a novel arginine methylation of a Ca2+-activated potassium transporter, KCa3.1, which regulates T cell fate by ensuring optimal Ca2+-mediated NFAT1 (NFATc2) signaling. Ablation of arginine methylation in KCa3.1 rendered T cells dysfunctional, associated with increased NFAT1 activity and markers of T cell exhaustion. Acute Met supplementation at early stages of tumour development improved T cell function, leading to better tumour control and animal survival. This study thus identifies a novel mechanism by which a nutrient deprived TME renders T cells dysfunctional. Funding Sources Supported by NIH AI123322, NIH CA231620, and ALSAC funding to Douglas R. Green, St. Jude Children’s Research Hospital. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)