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

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

Upon antigenic stimulation, antigen-specific naive T cells proliferate extensively and acquire different types of effector functions. To support cell growth and proliferation, activated T cells adapt their metabolism to ensure the generation of sufficient biomass and energy. Unlike quiescent T cells, which require little nutrients and mostly use oxidative phosphorylation (OXPHOS) for their energy supply, activated T cells consume large amounts of glucose, amino acids, and fatty acids and adjust their metabolic pathways toward increased glycolytic and glutaminolytic activity.

At the end of the immune response, most T cells undergo apoptosis, while a few survive as memory T cells that confer long-term protection. T cell survival is regulated by extrinsic and intrinsic factors. Prolonged or strong stimulation of the T cell receptor (TCR) of CD4+ and CD8+ T cells promotes “fitness” by enhancing survival and responsiveness to the homeostatic cytokines IL-7 and IL-15, which in turn sustain expression of anti-apoptotic proteins.

Metabolic activity is also critical to determine T cell fate and memory formation. For instance, triglyceride synthesis is central in IL-7-mediated survival of memory CD8+ T cells, while increased mitochondrial capacity endows T cells with a bioenergetic advantage for survival and recall responses. Mitochondrial fatty acid oxidation is required for the generation of memory T cells, while the mammalian target of rapamycin (mTOR), a central regulator of cell metabolism, has been shown to control T cell memory formation.

Metabolic fitness and T cell survival are particularly crucial in anti-tumor responses because nutrients are often scarce in the tumor microenvironment leading to T cell dysfunction, stress, and apoptosis. Depletion of glucose may decrease production of interferon (IFN)-γ and modulate the differentiation of regulatory T cells.

In addition, degradation of L-arginine by myeloid-derived suppressor cells leads to reduced expression of the CD3ζ chain, resulting in impaired T cell responsiveness. L-arginine is a versatile amino acid that serves as a building block for protein synthesis and as a precursor for multiple metabolites, including, polyamines, and nitric oxide (NO) that have strong immunomodulatory properties.

In this study, authors took advantage of recent developments in mass spectrometry  to obtain dynamic proteome and metabolome profiles of human primary naive T cells following activation and found several changes in metabolic pathways. In particular, they found that L-arginine controls glycolysis and mitochondrial activity and enhances T cell survival by interaction with transcriptional regulators. They identified three transcriptional regulators (BAZ1B, PSIP1, and TSN) that sensed L-arginine levels and promoted T cell survival.

Moreover, L-arginine enhanced the generation of central memory-like T (Tcm) cells with enhanced anti-tumor activity in a mouse model. Thus, intracellular L-arginine concentrations directly impact the metabolic fitness and survival capacity of T cells that are crucial for anti-tumor responses.




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