Cell 167, 829–842 (2016)

Credit: ELSEVIER

T cells undergo metabolic changes at various stages of maturation and activation, including an increased utilization of glycolysis upon activation from a quiescent state. In order to define critical molecular players involved in T cell metabolism changes, Geiger et al. performed proteomic and metabolomics analyses of activated T cells to find 2,824 proteins whose expression levels differed from those in quiescent T cells, as well as 49 metabolites that significantly increased and 14 metabolites that decreased in abundance upon activation. Several of these 14 metabolites belong to the same metabolic pathway, so the authors decided to focus on one, L-arginine (L-Arg). Experiments in which the authors added excess L-Arg to T cells or inhibited its degradation indicated that L-Arg can be internalized and can cause metabolic profile switches from glycolysis to oxidative phosphorylation, accompanied by increases in relevant enzymes. In addition, L-Arg limits T cell differentiation while promoting T cell survival; the latter phenomenon also occurs in vivo in mice, accompanied by increased antitumor activity. Further proteomic analysis of samples from donors found three transcriptional regulators, BAZ1B, PSIP1 and TSN, that were implicated in knockout experiments as mediating the L-Arg effect on T cell survival. These results suggest that L-Arg sensors act to transcriptionally regulate metabolic pathways that control T cell survival and differentiation.