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

1 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.
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: lanzavecchia@irb.usi.ch.

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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