T Cell Activation Depends on Extracellular Alanine

T cell stimulation is metabolically demanding. To exit quiescence, T cells rely on environmental nutrients, including glucose and the amino acids glutamine, leucine, serine, and arginine. The expression of transporters for these nutrients is tightly regulated and required for T cell activation. In c...

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Veröffentlicht in:Cell reports (Cambridge) Jg. 28; H. 12; S. 3011 - 3021.e4
Hauptverfasser: Ron-Harel, Noga, Ghergurovich, Jonathan M., Notarangelo, Giulia, LaFleur, Martin W., Tsubosaka, Yoshiki, Sharpe, Arlene H., Rabinowitz, Joshua D., Haigis, Marcia C.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Elsevier Inc 17.09.2019
Elsevier
Schlagworte:
alanine
metabolism
protein synthesis
T cell activation
T cells
protein synthesis
metabolism
alanine
T cell activation
T cells
ISSN:2211-1247, 2211-1247
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Zusammenfassung:T cell stimulation is metabolically demanding. To exit quiescence, T cells rely on environmental nutrients, including glucose and the amino acids glutamine, leucine, serine, and arginine. The expression of transporters for these nutrients is tightly regulated and required for T cell activation. In contrast to these amino acids, which are essential or require multi-step biosynthesis, alanine can be made from pyruvate by a single transamination. Here, we show that extracellular alanine is nevertheless required for efficient exit from quiescence during naive T cell activation and memory T cell restimulation. Alanine deprivation leads to metabolic and functional impairments. Mechanistically, this vulnerability reflects the low expression of alanine aminotransferase, the enzyme required for interconverting pyruvate and alanine, whereas activated T cells instead induce alanine transporters. Stable isotope tracing reveals that alanine is not catabolized but instead supports protein synthesis. Thus, T cells depend on exogenous alanine for protein synthesis and normal activation. [Display omitted] •Alanine is an essential amino acid for T cells to exit quiescence•Alanine deprivation during early activation leads to functional impairment•T cells do not catabolize alanine during early activation•Extracellular alanine supports protein synthesis In health, T lymphocytes are in a resting state. However, stimulation with their cognate antigen induces massive growth and proliferation. Ron-Harel et al. demonstrate that T cells rely on extracellular alanine for activation. Consumed alanine is used primarily for protein synthesis, and alanine deprivation inhibits T cell metabolism and effector functions.
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Conceptualization, N.R.H., J.M.G., A.H.S., J.D.R., M.C.H.; Methodology, N.R.H., J.M.G., G.N., M.W.L., A.H.S., J.D.R., M.C.H.; Investigation, N.R.H., J.M.G., G.N., M.W.L., Y.T.; Writing-Original Draft, N.R.H., J.M.G., J.D.R., M.C.H; Writing-Review & Editing, N.R.H., J.M.G., G.N., M.W.L., A.H.S., J.D.R., M.C.H.; Visualization, N.R.H., J.M.G., G.N., A.H.S., J.D.R., M.C.H.; Funding Acquisition, A.H.S., J.D.R., M.C.H.
These authors contributed equally to this work
Authors contribution
Current address: Faculty of Biology, Technion, Haifa, 3200003, Israel
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2019.08.034