L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity

Metabolic activity is intimately linked to T cell fate and function. Using high-resolution mass spectrometry, we generated dynamic metabolome and proteome profiles of human primary naive T cells following activation. We discovered critical changes in the arginine metabolism that led to a drop in int...

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Bibliographic Details
Published in:Cell 2016-10, Vol.167 (3), p.829-842.e13
Main Authors: Geiger, Roger, Rieckmann, Jan C., Wolf, Tobias, Basso, Camilla, Feng, Yuehan, Fuhrer, Tobias, Kogadeeva, Maria, Picotti, Paola, Meissner, Felix, Mann, Matthias, Zamboni, Nicola, Sallusto, Federica, Lanzavecchia, Antonio
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Animals
Arginine - metabolism
cancer immunotherapy
CD4-Positive T-Lymphocytes - immunology
CD4-Positive T-Lymphocytes - metabolism
DNA-Binding Proteins - metabolism
Gene Knockout Techniques
Glycolysis
Humans
Immunologic Memory
Immunomodulation
L-arginine
LiP-MS
Lymphocyte Activation
Melanoma, Experimental - immunology
metabolism
metabolite sensing
Metabolome
Mice
Mice, Inbred BALB C
Oxidative Phosphorylation
Proteome
Skin Neoplasms - immunology
T cell
T cell survival
Transcription Factors - metabolism
Transcription, Genetic
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Summary:Metabolic activity is intimately linked to T cell fate and function. Using high-resolution mass spectrometry, we generated dynamic metabolome and proteome profiles of human primary naive T cells following activation. We discovered critical changes in the arginine metabolism that led to a drop in intracellular L-arginine concentration. Elevating L-arginine levels induced global metabolic changes including a shift from glycolysis to oxidative phosphorylation in activated T cells and promoted the generation of central memory-like cells endowed with higher survival capacity and, in a mouse model, anti-tumor activity. Proteome-wide probing of structural alterations, validated by the analysis of knockout T cell clones, identified three transcriptional regulators (BAZ1B, PSIP1, and TSN) that sensed L-arginine levels and promoted T cell survival. Thus, intracellular L-arginine concentrations directly impact the metabolic fitness and survival capacity of T cells that are crucial for anti-tumor responses. [Display omitted] •Dataset on dynamic metabolome/proteome profiles of activated human naive T cells•Intracellular L-arginine levels regulate several metabolic pathways in T cells•T cells with increased L-arginine display enhanced survival and anti-tumor activity•LiP-MS identified proteins that are structurally modified by high L-arginine levels Metabolomic and proteomic profiling unveil intracellular L-arginine as a crucial regulator of metabolic fitness, survival capacity, and anti-tumor activity of central memory T cells.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2016.09.031