Abstract
It is well established that cholesterol and glycosphingolipids are enriched in the plasma membrane (PM) and form signaling platforms called lipid rafts, essential for T-cell activation and function. Moreover, changes in PM lipid composition affect the biophysical properties of lipid rafts and have a role in defining functional T-cell phenotypes. Here, we review the role of transcriptional regulators of lipid metabolism including liver X receptors α/β, peroxisome proliferator-activated receptor γ, estrogen receptors α/β (ERα/β), and sterol regulatory element-binding proteins in T-cells. These receptors lie at the interface between lipid metabolism and immune cell function and are endogenously activated by lipids and/or hormones. Importantly, they regulate cellular cholesterol, fatty acid, glycosphingolipid, and phospholipid levels but are also known to modulate a broad spectrum of immune responses. The current evidence supporting a role for lipid metabolism pathways in controlling immune cell activation by influencing PM lipid raft composition in health and disease, and the potential for targeting lipid biosynthesis pathways to control unwanted T-cell activation in autoimmunity is reviewed.
Highlights
CD4+ T-cells play a central role in the adaptive immune system
Reducing plasma membrane (PM) order with the oxysterol 7-ketocholesterol is alone sufficient to alter the functional phenotype of T-cells [9]. These advances in understanding the link between PM lipids and T-cell function are supported by state-of-the-art microscopy techniques including super-resolution fluorescence microscopy that have revolutionized the visualization of PM lipids and membrane order [24,25,26,27,28]
More efficient atheroprotective high-density lipoprotein (HDL) is produced during high E2 phases of the menstrual cycle, resulting in increased cholesterol efflux capacity [46]. This may alter the levels of cholesterol in the PM and the composition of PM lipid rafts, as has been shown in antigen-presenting cells (APCs) [47], thereby influencing proinflammatory signaling. This effect on lipid metabolism is mediated by estrogen receptor-α (ERα) control of LXRα transcriptional activity through the binding of the receptors to promoters or enhancer regions of LXRα target genes involved in cholesterol homeostasis
Summary
CD4+ T-cells play a central role in the adaptive immune system Upon activation, they proliferate, traffic to inflamed sites, and acquire functions that mediate the immune response against infection and malignancy [1]. Reducing PM order with the oxysterol 7-ketocholesterol is alone sufficient to alter the functional phenotype of T-cells [9] These advances in understanding the link between PM lipids and T-cell function are supported by state-of-the-art microscopy techniques including super-resolution fluorescence microscopy that have revolutionized the visualization of PM lipids and membrane order [24,25,26,27,28]. The increasing evidence describing defects in T-cell PM lipid rafts associated with abnormal T-cell function in autoimmunity makes this an attractive therapeutic area [29, 30]
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