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

Summary

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.

Graphical Abstract

Highlights

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  Dataset on dynamic metabolome/proteome profiles of activated human naive T cells

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  Intracellular L-arginine levels regulate several metabolic pathways in T cells

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  T cells with increased L-arginine display enhanced survival and anti-tumor activity

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  LiP-MS identified proteins that are structurally modified by high L-arginine levels

Abstract

Metabolomic and proteomic profiling unveil intracellular L-arginine as a crucial regulator of metabolic fitness, survival capacity, and anti-tumor activity of central memory T cells.