T lymphocyte regulation by mevalonate metabolism.

Abstract

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.

• Authors: Martin Thurnher, Georg Gruenbacher
• Journal: Science signaling (Sci Signal) Vol. 8 Issue 370 Pg. re4 (Mar 31 2015) ISSN: 1937-9145 [Electronic] United States
• PMID: 25829448 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• Gonadal Steroid Hormones
• Ubiquinone
• Cholesterol
• Mevalonic Acid

Topics

• 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, metabolism)
• Ubiquinone (metabolism)