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. Epub 2016 Oct 13.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Arginine / metabolism*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • DNA-Binding Proteins / metabolism
  • Gene Knockout Techniques
  • Glycolysis
  • Humans
  • Immunologic Memory
  • Immunomodulation*
  • Lymphocyte Activation*
  • Melanoma, Experimental / immunology*
  • Metabolome
  • Mice
  • Mice, Inbred BALB C
  • Oxidative Phosphorylation
  • Proteome
  • Skin Neoplasms / immunology*
  • Transcription Factors / metabolism
  • Transcription, Genetic


  • Adaptor Proteins, Signal Transducing
  • BAZ1B protein, human
  • DNA-Binding Proteins
  • PSIP1 protein, human
  • Proteome
  • TSN protein, human
  • Transcription Factors
  • Arginine