Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation

Abstract

Summary T lymphocytes regulate nutrient uptake to meet the metabolic demands of immune activation. The present study shows that the intracellular supply of large neutral amino acids (LNAAs) in T cells is regulated by pathogen and the T cell antigen receptor (TCR). A single System L transporter, Slc7a5, mediated LNAA uptake in activated T cells. Slc7a5-null T cells could not metabolically reprogram in response to antigen and failed clonal expansion and effector differentiation. The metabolic catastrophe caused by Slc7a5 loss reflects the requirement for sustained uptake of the LNAA leucine for activation of mammalian target of rapamycin complex 1 (mTORC1) and for expression of c-myc. Pathogen control of System L transporters is thus a critical metabolic checkpoint for T cells.

Dynamin 2-dependent endocytosis sustains T-cell receptor signaling and drives metabolic reprogramming in T lymphocytes

“…Availability of nutrients is another critical requirement for mTORC1 activation in T cells. TCR signaling increases amino acid uptake, which is essential for mTORC1 activation (18). We therefore determined surface expression of the amino acid transporter CD98.…”

Cytosolic Branched Chain Aminotransferase (BCATc) Regulates mTORC1 Signaling and Glycolytic Metabolism in CD4+ T Cells

“…Interestingly, the BCAT1 gene has been shown to be a direct target for c-myc activation (55). Recently, c-myc has been shown to play a vital role in CD8 ϩ T cell effector function (22). In these studies, c-myc was shown to up-regulate the glycolytic machinery necessary for T cell activation (22).…”

“…Recently, c-myc has been shown to play a vital role in CD8 ϩ T cell effector function (22). In these studies, c-myc was shown to up-regulate the glycolytic machinery necessary for T cell activation (22). The fact that BCATc Ϫ/Ϫ T cells demonstrate enhanced glycolysis suggests that up-regulation of BCATc represents a negative feedback loop in this pathway.…”

“…There is accumulating evidence that Leu and Leu cellular import are involved in T cell activation (21)(22)(23). Sinclair et al (22) showed that the System L transporter, Slc7a5, is a key factor in T cell metabolic reprogramming that directs Leu transport and controls mTORC1 activity (22).…”

Tsc1 promotes the differentiation of memory CD8 + T cells via orchestrating the transcriptional and metabolic programs

“…Naïve and memory T cells use catabolic metabolism via oxidative phosphorylation, especially fatty acid oxidation, to produce ATP for their survival. In contrast, antigen-stimulated T cells switch to anabolism to support their rapid proliferation through up-regulating expression of genes involved in multiple metabolic pathways, including glycolysis, fatty acid and cholesterol biosynthesis, and amino acid transport (7)(8)(9)(10). Emerging studies indicate that distinct metabolic pathways contribute to the fate decisions of effector and memory T cells.…”