title: L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity.
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.
authors.affiliation: 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.
authors.forename: Roger
authors.initials: R
authors.lastname: Geiger
authors.affiliation: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
authors.forename: Jan C
authors.initials: JC
authors.lastname: Rieckmann
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland; Institute of Microbiology, ETH Zurich, Zurich 8093, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Wolf
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Switzerland.
authors.forename: Camilla
authors.initials: C
authors.lastname: Basso
authors.affiliation: Institute of Biochemistry, ETH Zurich, Zurich 8093, Switzerland.
authors.forename: Yuehan
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Fuhrer
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Kogadeeva
authors.affiliation: Institute of Biochemistry, ETH Zurich, Zurich 8093, Switzerland.
authors.forename: Paola
authors.initials: P
authors.lastname: Picotti
authors.affiliation: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Meissner
authors.affiliation: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Zamboni
authors.affiliation: 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.
authors.forename: Federica
authors.initials: F
authors.lastname: Sallusto
authors.affiliation: 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.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lanzavecchia
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D055786:Gene Knockout Techniques; D006019:Glycolysis; D006801:Humans; D007156:Immunologic Memory; D056747:Immunomodulation; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology*; D055442:Metabolome; D051379:Mice; D008807:Mice, Inbred BALB C; D010085:Oxidative Phosphorylation; D020543:Proteome; D012878:Skin Neoplasms / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000092468:Bromodomain Containing Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001120:Arginine; D004268:DNA-Binding Proteins; D020543:Proteome; D014157:Transcription Factors; C116750:BAZ1B protein, human; D000092468:Bromodomain Containing Proteins; C504649:PSIP1 protein, human; C095563:TSN protein, human
keywords: L-arginine; LiP-MS; T cell; T cell survival; cancer immunotherapy; metabolism; metabolite sensing; metabolome; proteome