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.
| Original language | English |
|---|---|
| Journal | Cell |
| Volume | 167 |
| Issue number | 3 |
| Pages (from-to) | 829-842.e13 |
| ISSN | 0092-8674 |
| DOIs | |
| Publication status | Published - 20 Oct 2016 |
| Externally published | Yes |
Keywords
- 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
- Journal Article
- Research Support, Non-U.S. Gov't