2. Academic Validation
  3. L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity

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

  • Cell. 2016 Oct 20;167(3):829-842.e13. doi: 10.1016/j.cell.2016.09.031.
Roger Geiger 1,  Jan C Rieckmann 2,  Tobias Wolf 3,  Camilla Basso 4,  Yuehan Feng 5,  Tobias Fuhrer 6,  Maria Kogadeeva 6,  Paola Picotti 5,  Felix Meissner 2,  Matthias Mann 2,  Nicola Zamboni 6,  Federica Sallusto 7,  Antonio Lanzavecchia 8
Affiliations

Affiliations

  • 1 Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland; Institute of Microbiology, ETH Zurich, Zurich 8093, Switzerland. Electronic address: [email protected].
  • 2 Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
  • 3 Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland; Institute of Microbiology, ETH Zurich, Zurich 8093, Switzerland.
  • 4 Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland.
  • 5 Institute of Biochemistry, ETH Zurich, Zurich 8093, Switzerland.
  • 6 Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland.
  • 7 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.
  • 8 Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland; Institute of Microbiology, ETH Zurich, Zurich 8093, Switzerland. Electronic address: [email protected].
PMID: 27745970 DOI: 10.1016/j.cell.2016.09.031
Abstract

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.

Keywords

L-arginine; LiP-MS; T cell; T cell survival; cancer immunotherapy; metabolism; metabolite sensing; metabolome; proteome.

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