Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation
Open accessAbstract
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.
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TCR ligation promotes the coordinated up-regulation of glucose and amino acid transporters, facilitating nutrient uptake and T cell blastogenesis.
“TCR ligation promotes the coordinated up-regulation of glucose and amino acid transporters (6–8), facilitating nutrient uptake and T cell blastogenesis.”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [8]
TCR signaling directs the metabolic reprogramming of naïve T cells.
“T cell receptor (TCR) signaling directs the metabolic reprogramming of naïve T cells.”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [8]
TCR engagement leads to expression of Slc7a5, an amino acid transporter mediating import of large neutral amino acids such as leucine.
“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).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [8]
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- Authors
- Sinclair, L. V., Rolf, J., Emslie, E., Shi, Y.-B., Taylor, P. M., & Cantrell, D. A.
- Affiliations
- University of Dundee (GB)
- National Institutes of Health (US)
- Corresponding author
- Cantrell, Doreen A
- Venue
- Nature Immunology
- Published
- 2013-03-24
- Volume
- 14
- Issue
- 5
- Pages
- 500-508
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC3672957
- OpenAlex
- W1993023349
- Cited by
- 930
- References
- 43
- Citations by year
- 2026: 66 · 2025: 83 · 2024: 85 · 2023: 79 · 2022: 89 · 2021: 85 · 2020: 92 · 2019: 82 · 2018: 57 · 2017: 67 · 2016: 48 · 2015: 53 · 2014: 32 · 2013: 12
- FWCI
- 22.62
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-12-18)
- Open access
- green
- europepmc.org
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Funders
- Wellcome Trust (097418/Z/11/Z, 065975, WT094226, 097418)
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- T cell activation, amino acid transport, metabolic reprogramming, T cell receptor signaling, mTORC1, c-Myc, SLC7A5, leucine uptake, large neutral amino acids, effector T cell differentiation, clonal expansion, nutrient uptake
- MeSH terms
- Animals, Cell Differentiation, Cytotoxicity, Immunologic, Interferon-gamma, Interleukin-2, Mice, Inbred C57BL, Mice, Mutant Strains, T-Lymphocytes, Cytotoxic, Up-Regulation, Receptors, Antigen, T-Cell, alpha-beta, Protein Transport, Amino Acids, Neutral, Large Neutral Amino Acid-Transporter 1, Cell Proliferation, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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