T lymphocyte regulation by mevalonate metabolism

• Published in: Science signaling 2015-03, Vol.8 (370), p.re4-re4
• Main Authors: Thurnher, Martin, Gruenbacher, Georg
• Format: Article
• Language: English
• Subjects: Cholesterol - metabolism; Glycolysis; Gonadal Steroid Hormones - metabolism; Homeostasis - immunology; Humans; Lymphocyte Activation - immunology; Metabolic Networks and Pathways - immunology; Mevalonic Acid - metabolism; Models, Immunological; Oxidative Phosphorylation; Protein Prenylation - immunology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Ubiquinone - metabolism
• ISSN: 1945-0877; 1937-9145
• DOI: 10.1126/scisignal.2005970

Whereas resting T cells, which have low metabolic requirements, use oxidative phosphorylation (OXPHOS) to maximize their generation of ATP, activated T cells, similar to tumor cells, shift metabolic activity to aerobic glycolysis, which also fuels mevalonate metabolism. Both sterol and nonsterol derivatives of mevalonate affect T cell function. The intracellular availability of sterols, which is dynamically regulated by different classes of transcription factors, represents a metabolic checkpoint that modulates T cell responses. The electron carrier ubiquinone, which is modified with an isoprenoid membrane anchor, plays a pivotal role in OXPHOS, which supports the proliferation of T cells. Isoprenylation also mediates the plasma membrane attachment of the Ras, Rho, and Rab guanosine triphosphatases, which are involved in T cell immunological synapse formation, migration, proliferation, and cytotoxic effector responses. Finally, multiple phosphorylated mevalonate derivatives can act as danger signals for innate-like γδ T cells, thus contributing to the immune surveillance of stress, pathogens, and tumors. We highlight the importance of the mevalonate pathway in the metabolic reprogramming of effector and regulatory T cells.