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

  • Geiger R Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland; Institute of Microbiology, ETH Zurich, Zurich 8093, Switzerland. Electronic address: roger.geiger@irb.usi.ch.
  • Rieckmann JC Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
  • Wolf T Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland; Institute of Microbiology, ETH Zurich, Zurich 8093, Switzerland.
  • Basso C Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland.
  • Feng Y Institute of Biochemistry, ETH Zurich, Zurich 8093, Switzerland.
  • Fuhrer T Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland.
  • Kogadeeva M Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland.
  • Picotti P Institute of Biochemistry, ETH Zurich, Zurich 8093, Switzerland.
  • Meissner F Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
  • Mann M Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
  • Zamboni N Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland.
  • Sallusto F Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland; Center of Medical Immunology, Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland.
  • Lanzavecchia A Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland; Institute of Microbiology, ETH Zurich, Zurich 8093, Switzerland. Electronic address: lanzavecchia@irb.usi.ch.
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  • 2016-10-18
Published in:
  • Cell. - 2016
L-arginine
LiP-MS
T cell
T cell survival
cancer immunotherapy
metabolism
metabolite sensing
metabolome
proteome
Adaptor Proteins, Signal Transducing
Animals
Arginine
CD4-Positive T-Lymphocytes
DNA-Binding Proteins
Gene Knockout Techniques
Glycolysis
Humans
Immunologic Memory
Immunomodulation
Lymphocyte Activation
Melanoma, Experimental
Metabolome
Mice
Mice, Inbred BALB C
Oxidative Phosphorylation
Proteome
Skin Neoplasms
Transcription Factors
Transcription, Genetic
English 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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  • English
Open access status
hybrid
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Persistent URL
https://sonar.ch/global/documents/36785
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