Antigen receptor control of amino acid transport coordinates the metabolic re-programming that is essential for T cell differentiation

By Linda V. Sinclair, J. Rolf, E. Emslie, Yunbo Shi, P. Taylor, D. Cantrell. Nature Immunology, 2013

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T lymphocytes must regulate nutrient uptake to meet the metabolic demands of an immune response. Here we show that the intracellular supply of large neutral amino acids (LNAAs) in T cells was regulated by pathogens and the T cell antigen receptor (TCR). T cells responded to antigen by upregulating expression of many amino-acid transporters, but a single System L ('leucine-preferring system') transporter, Slc7a5, mediated uptake of LNAAs in activated T cells. Slc7a5-null T cells were unable to metabolically reprogram in response to antigen and did not undergo clonal expansion or effector differentiation. The metabolic catastrophe caused by loss of Slc7a5 reflected the requirement for sustained uptake of the LNAA leucine for activation of the serine-threonine kinase complex mTORC1 and for expression of the transcription factor c-Myc. Control of expression of the System L transporter by pathogens is thus a critical metabolic checkpoint for T cells.

Subfields: Biochemistry, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8e13d77ba1fc5875fcf63b8216729ab76fcbf9fe

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Citations in the corpus

Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity (2020, background): “We observed metabolic signatures enriched with CD that have been correlated with T cell activation, including sugar and amino acid metabolism (Figure 3K; Geiger et al., 2016; MacIver et al., 2013; Sinclair et al., 2013;Wei et al., 2017).”
The Glucose Transporter Glut1 is Selectively Essential for CD4 T Cell Activation and Effector Function (2014, neutral): “These metabolic programs provide distinct metabolites (MacIver et al., 2013), signaling through the mammalian target of rapamycin complex 1 (mTORC1) pathway (Sinclair et al., 2013), and cytokine production (Cham and Gajewski, 2005; Chang et al., 2013).”
Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013, background): “Recently, it was found that engagement of the TCR leads to the expression of Slc7a5, an amino acid transporter that mediates the import of large neutral amino acids, such as leucine (8).”
Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation (2014, neutral): “expression of Slc7a5 and CD98, components of a major leucine transporter in T cells (Sinclair et al., 2013).”
The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. (2015, background): “Upon activation, naive T cells shift to- ward a pro-growth metabolic program characterized by increased glucose and amino acid metabolism (Carr et al., 2010; Frauwirth et al., 2002; Nakaya et al., 2014; Sinclair et al., 2013; Wang et al., 2011).”
The PI3K pathway in human disease (2017, positive): “Similarly, in activated CD8 T cells, leucine uptake via the system L amino acid transporter Slc7a5 is required for mTORC1 activity, c-Myc translation, and metabolic reprogramming (Sinclair et al., 2013), whereas PI3K/AKT signaling is dispensable for these outcomes”
L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity (2016, background): “…(OXPHOS) for their energy supply, activated T cells consume large amounts of glucose, amino acids, and fatty acids and adjust their metabolic pathways toward increased glycolytic and glutaminolytic activity (Blagih et al., 2015; Rolf et al., 2013; Sinclair et al., 2013; Wang et al., 2011).”
Metabolic Instruction of Immunity (2017, positive): “Glutamine controls mTOR activation in T cells and macrophages and is also a key substrate for protein O-GlcNAcylation and synthesis of S-2HG that regulate effector T cell function and differentiation (Sinclair et al., 2013; Swamy et al., 2016; Tyrakis et al., 2016).”
Unraveling the Complex Interplay Between T Cell Metabolism and Function (2018, background): “Inheritance of high mTORC1 activity is associated with increased expression of the large neutral amino acid transporter CD98 (33, 34), expression of which is critical for clonal expansion and Te cell differentiation (35) (Figure 2).”