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

TLDR

Metabolic activity is intimately linked to T cell fate and function. High‑resolution mass spectrometry was used to generate dynamic metabolome and proteome profiles of human primary naive T cells after activation, and proteome‑wide probing identified three transcriptional regulators that sensed L‑arginine levels and promoted T cell survival. Elevating intracellular L‑arginine levels shifts activated T cells from glycolysis to oxidative phosphorylation, promotes central memory‑like cell generation with enhanced survival, and improves anti‑tumor activity, while reduced L‑arginine impairs metabolic fitness and survival capacity.

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.