Glutamine Uptake and Metabolism Are Coordinately Regulated by ERK/MAPK During T Lymphocyte Activation

By E. Carr, A. Kelman, Glendon S. Wu, Ravindra Gopaul, E. Senkevitch, Anahit Aghvanyan, Achmed M. Turay, Kenneth A. Frauwirth. Journal of Immunology, 2010

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Activation of a naive T cell is a highly energetic event, which requires a substantial increase in nutrient metabolism. Upon stimulation, T cells increase in size, rapidly proliferate, and differentiate, all of which lead to a high demand for energetic and biosynthetic precursors. Although amino acids are the basic building blocks of protein biosynthesis and contribute to many other metabolic processes, the role of amino acid metabolism in T cell activation has not been well characterized. We have found that glutamine in particular is required for T cell function. Depletion of glutamine blocks proliferation and cytokine production, and this cannot be rescued by supplying biosynthetic precursors of glutamine. Correlating with the absolute requirement for glutamine, T cell activation induces a large increase in glutamine import, but not glutamate import, and this increase is CD28-dependent. Activation coordinately enhances expression of glutamine transporters and activities of enzymes required to allow the use of glutamine as a Krebs cycle substrate in T cells. The induction of glutamine uptake and metabolism requires ERK function, providing a link to TCR signaling. Together, these data indicate that regulation of glutamine use is an important component of T cell activation. Thus, a better understanding of glutamine sensing and use in T cells may reveal novel targets for immunomodulation.

Subfields: Cancer Research, Immunology

View Paper: https://www.semanticscholar.org/paper/9514dfab1ab702b3f5c09e302b71fc110cd8fa50

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Citations in the corpus

Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation (2014, positive): “T cell activation triggers the induction of two glutamine transporters, SNAT1 and SNAT2, which are associated with enhanced glutamine uptake measured at 24 hr postactivation (Carr et al., 2010).”
The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “In natural T cells, glutamine and glucose import are CD28 dependent (Carr et al., 2010; Frauwirth et al., 2002).”
T cell lipid peroxidation induces ferroptosis and prevents immunity to infection (2015, background): “ERK1/2 phosphorylation upon TCR triggering depends on the generation of hydrogen peroxide and stimulates glutamine uptake (Devadas et al., 2002; Carr et al., 2010).”
T Cell Dysfunction in Cancer (2018, background): “First, glutamine is essential for T cell activation and differentiation, but is also often depleted from the TME due to its use as primary fuel for tumor cells (Altman et al., 2016; Carr et al., 2010).”
Unraveling the Complex Interplay Between T Cell Metabolism and Function (2018, background): “In addition, the cell surface translocation of Glut1 and the glutamine transporters sodium-coupled neutral amino acid transporter (SNAT)1; SNAT2; and alanine-, serine-, and cysteine-preferring transporter 2 (ASCT2), which are expressed by activated Te cells, requires N-linked glycosylation, supporti”
Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism (2018, background): “In addition to increased use of glucose in activated effector T cells, glutamine uptake andglutaminolysis are also upregulated (Carr et al., 2010; Wang et al., 2011).”
T cell metabolism drives immunity (2015, background): “T cells increase the expression of glutamine transporters, and their deletion impairs the transition to an effector T cell (Carr et al., 2010; Sinclair et al., 2013).”
Metabolic Regulation of Immune Responses (2014, background): “As reported previously, T cell proliferation and survival was dependent on glycolysis when cells were cultured in medium containing glucose and glutamine (86, 91, 96, 98).”
Antigen receptor control of amino acid transport coordinates the metabolic re-programming that is essential for T cell differentiation (2013, neutral): “Inhibitor treatment was as follows: mTORC1 inhibitor rapamycin (20 nM; Calbiochem); MEK inhibitor PD184352 (2 μM; synthesized in-house by the DSTT); System L inhibitor BCH (2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid; 50 mM; Sigma); and CsA (100 nM; Sigma).”
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 transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation (2011, background): “Early studies have implicated the involvement of ERK-, AKT-, and mTOR-mediated signaling pathways in regulating T cell metabolism (Carr et al., 2010; Frauwirth et al., 2002; Pearce et al., 2009).”
CD8+ T Cells: Foot Soldiers of the Immune System (2011, positive): “Recently, it has been demonstrated that in addition to costimulatory signals, such as CD28-induced PI-3K-Akt-mTOR signaling (Michalek and Rathmell, 2010), TCR-ERK signaling is required for enhanced glycolysis and glucose plus glutamine uptake (Carr et al., 2010; Marko et al., 2010).”