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

• Published in: Cell Vol. 167; no. 3; pp. 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: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-10-2016; Cell Press
• 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; metabolite sensing; T cell; T cell survival; cancer immunotherapy; metabolism; L-arginine; LiP-MS; metabolome; proteome
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2016.09.031

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.
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•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.