The metabolic liability of T cell activation

To exit quiescence, T cells rely on environmental nutrients, to simultaneously fuel multiple metabolic pathways, which often share common precursors. Such nutrients include: glucose and the amino acids glutamine, leucine, serine and arginine. Controlling the uptake to these nutrients is a key mechanism for regulating T cell activation. In contrast to these amino acids, which are either essential or require multi-step biosynthetic processes, the amino acid alanine can be made from pyruvate in a single transamination step. Nevertheless, we found that extracellular alanine is essential for T cells to exit quiescence, as they lack expression of alanine aminotransferase, the enzyme that interconverts pyruvate and alanine. Alanine deprivation leads to wide-ranging metabolic changes and functional impairment in T cells. Interestingly, consumed alanine is not catabolized but is instead directly used by T cells for protein synthesis. Taken together, our findings suggest that T cells may be sensitive to changing alanine concentrations during physiological or disease states. Accordingly, interventions that target alanine uptake and synthesis may provide a new therapeutic strategy for modulating T cell function.