L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity
What this study shows
Tracking metabolites and proteins in activated human T cells, the authors found intracellular L-arginine falls sharply after activation even in 1 mM medium, because uptake and conversion to ornithine, proline and spermidine rise. Raising L-arginine shifted metabolism from glycolysis towards oxidative phosphorylation, increased oxygen consumption and spare respiratory capacity, and produced central-memory-like cells (CCR7 and CD62L high, less IFN-gamma) with greater survival capacity; blocking arginase gave the same survival gain at physiological 150 uM L-arginine. Limited-proteolysis mass spectrometry plus knockout clones identified three nuclear proteins, BAZ1B, PSIP1 and TSN, that sense L-arginine and contribute to the survival programme. In mice, oral L-arginine raised serum levels from about 160 uM to 700 uM and roughly doubled intracellular L-arginine in activated T cells, and L-arginine-treated OT-I cells slowed B16-OVA growth and extended survival. The authors report explicitly that the survival effect was independent of mTOR: L-arginine did not change S6K1 or 4E-BP phosphorylation, and rapamycin, while also improving survival, changed metabolism in an entirely different way. Boundary: mostly human T cells in culture plus mouse transfer and transplantable-tumour models; the dietary arm is a mouse supplementation experiment, not a human trial, and mTOR enters only as a negative control.
At a glance
| Evidence type | M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Human primary naive CD4 and CD8 T cells with high-resolution metabolomics, proteomics and limited-proteolysis mass spectrometry, plus CRISPR knockout T-cell clones; mouse HA-TCR transgenic transfers with oral L-arginine, and B16-OVA melanoma with OT-I transfer) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is. |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Human primary naive CD4 and CD8 T cells with high-resolution metabolomics, proteomics and limited-proteolysis mass spectrometry, plus CRISPR knockout T-cell clones; mouse HA-TCR transgenic transfers with oral L-arginine, and B16-OVA melanoma with OT-I transfer |
| Journal | Cell |
| Year | 2016 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1016/j.cell.2016.09.031 · PMID 27745970 · Free full text (PMC5075284) |
Extracted findings
These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.
| Intervention | L-arginine supplementation in vitro (3 to 4 mM) and by oral gavage in mice; arginase inhibition; CRISPR knockout of BAZ1B, PSIP1 and TSN; rapamycin 100 nM as comparator |
| Target | Intracellular L-arginine levels and T-cell metabolic programme, survival and memory phenotype |
| Model | Human and mouse |
| Effect | Higher intracellular L-arginine shifted T cells from glycolysis to oxidative phosphorylation and increased survival, memory-like phenotype and anti-tumour activity, without changing mTORC1 readouts |
In the Atlas
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- mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex (2007)
- mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation (2013)
- The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity (2006)
- Sexual Dimorphism in Placental mTORC1 Signaling, Amino Acid Transport, and Mitochondrial Respiration at Term. (2026)
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