Decoding the crosstalk between mevalonate metabolism and T cell function

Abstract

SummaryThe mevalonate pathway is an essential metabolic pathway in T cells regulating development, proliferation, survival, differentiation, and effector functions. The mevalonate pathway is a complex, branched pathway composed of many enzymes that ultimately generate cholesterol and nonsterol isoprenoids. T cells must tightly control metabolic flux through the branches of the mevalonate pathway to ensure sufficient isoprenoids and cholesterol are available to meet cellular demands. Unbalanced metabolite flux through the sterol or the nonsterol isoprenoid branch is metabolically inefficient and can have deleterious consequences for T cell fate and function. Accordingly, there is tight regulatory control over metabolic flux through the branches of this essential lipid synthetic pathway. In this review we provide an overview of how the branches of the mevalonate pathway are regulated in T cells and discuss our current understanding of the relationship between mevalonate metabolism, cholesterol homeostasis and T cell function.

T cell cholesterol transport is a metabolic checkpoint that links intestinal immune responses to dietary lipid absorption

“…Of note, expression of genes linked to sterol synthesis and efflux were not altered in A ΔCD4 Th17 cells, suggesting that intracellular cholesterol homeostasis is largely maintained (Fig. 5e) (42). We conclude that Aster-A functions to restrain TCR nanoclustering and signaling in Th17 cells by removing PM cholesterol.…”

Farnesyltransferase-inhibitors exert in vitro immunosuppressive capacity by inhibiting human B-cells

“…Puniya et al recently predicted in a computational model based on multi-omic data Farnesyl-diphosphate farnesyltransferase 1 (FDFT1) as drug target candidate in T-cell mediated diseases such as RA and multiple sclerosis ( 20 ). FDFT1 is a key enzyme in the mevalonate metabolism of T-cells and the corresponding metabolites of this pathway regulate T-cell activation ( 21 ). Thus, FTI may offer the opportunity for targeted treatment of immune cells.…”