Asparagine enhances LCK signalling to potentiate CD8+ T-cell activation and anti-tumour responses

LCK senses asparagine for T cell activation

“…SLC1A5 expression increases with T cell activation 5 , which correlates with the increase in intracellular asparagine. Pharmacological inhibition or ablation by short interfering RNA of SLC1A5 reduced both intracellular asparagine and glutamine 3 . Thus, asparagine and glutamine likely worked in concert to support T cell activation, and asparagine promoted CD8 + T cell activation when glutamine levels were limiting 3 .…”

“…Although the roles of several amino acids have been examined, including arginine, leucine, glutamine, alanine, methionine, and serine, our knowledge of how additional amino acids contribute to T cell activity and how T cells precisely sense amino acids to trigger downstream events is limited. In this issue of Nature Cell Biology, Wu et al have expanded upon the known roles of amino acids in T cell biology by identifying the SRC-family tyrosine kinase LCK as an asparagine sensor 3 (Fig. 1).…”

“…Amino acid catabolism contributes to metabolic processes, including glutaminolysis and serine-glycine-one-carbon metabolism, that support de novo nucleotide synthesis and energy production required for T cell effector responses 1,4,12 . While isotope tracing of [ 15 N]asparagine revealed that asparagine was not further metabolised for amino acid and purine synthesis, T cells activated in the presence of asparagine were enriched in many intracellular metabolites, suggesting that asparagine may support metabolic reprogramming in T cells 3 . This metabolic reprogramming was likely mediated by enhanced TCR-induced mTORC1 signalling in the presence of asparagine 1,3,8 .…”

“…While isotope tracing of [ 15 N]asparagine revealed that asparagine was not further metabolised for amino acid and purine synthesis, T cells activated in the presence of asparagine were enriched in many intracellular metabolites, suggesting that asparagine may support metabolic reprogramming in T cells 3 . This metabolic reprogramming was likely mediated by enhanced TCR-induced mTORC1 signalling in the presence of asparagine 1,3,8 . Interestingly, rapamycin, an mTORC1 inhibitor, only partially reduced asparagine-mediated T cell activation, suggesting a potential mTORC1-independent mechanism by which asparagine promotes T cell activation.…”

“…Overall, the work by Wu et al identifies LCK as a novel intracellular asparagine sensor whose sensing modulates TCR-mediated CD8 + T cell activation and effector responses to pathogens and tumour cells. Wu et al additionally highlight a potential role for LCK sensing of asparagine in cancer immunosurveillance, as some tumour cells can secrete asparagine 3 . Whether asparagine promotes metabolic rewiring (for example, elevated oxidative phosphorylation) to favour memory T cell formation and enhance the persistence and function of tumour-infiltrating lymphocytes is of interest for future investigation.…”