Transcriptional Regulation of T-Cell Lipid Metabolism: Implications for Plasma Membrane Lipid Rafts and T-Cell Function

Plasma membrane lipid rafts are heterogeneous cholesterol and glycosphingolipid (GSL)-enriched microdomains, within which the tight packing of cholesterol with the saturated-acyl chains of GSLs creates a region of liquid-order relative to the surrounding disordered membrane. Thus lipid rafts govern the lateral mobility and interaction of membrane proteins and regulate a plethora of signal transduction events, including T-cell antigen receptor (TCR) signalling. The pathways regulating homoeostasis of membrane cholesterol and GSLs are tightly controlled and alteration of these metabolic processes coincides with immune cell dysfunction as is evident in atherosclerosis, cancer and autoimmunity. Indeed, membrane lipid composition is emerging as an important factor influencing the ability of cells to respond appropriately to microenvironmental stimuli. Consequently, there is increasing interest in targeting membrane lipids or their metabolic control as a novel therapeutic approach to modulate immune cell behaviour and our recent work demonstrates that this is a promising strategy in T-cells from patients with the autoimmune disease systemic lupus erythematosus (SLE).

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LXR directly regulates glycosphingolipid synthesis and affects human CD4+ T cell function

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2017394118 ◽

2021 ◽

Vol 118 (21) ◽

pp. e2017394118

Author(s):

Kirsty E. Waddington ◽

George A. Robinson ◽

Beatriz Rubio-Cuesta ◽

Eden Chrifi-Alaoui ◽

Sara Andreone ◽

...

Keyword(s):

T Cells ◽

Plasma Membrane ◽

Lipid Metabolism ◽

T Cell ◽

T Cell Activation ◽

Cell Function ◽

Cholesterol Metabolism ◽

T Cell Subsets ◽

Lipid Order ◽

T Cell Function

The liver X receptor (LXR) is a key transcriptional regulator of cholesterol, fatty acid, and phospholipid metabolism. Dynamic remodeling of immunometabolic pathways, including lipid metabolism, is a crucial step in T cell activation. Here, we explored the role of LXR-regulated metabolic processes in primary human CD4+ T cells and their role in controlling plasma membrane lipids (glycosphingolipids and cholesterol), which strongly influence T cell immune signaling and function. Crucially, we identified the glycosphingolipid biosynthesis enzyme glucosylceramide synthase as a direct transcriptional LXR target. LXR activation by agonist GW3965 or endogenous oxysterol ligands significantly altered the glycosphingolipid:cholesterol balance in the plasma membrane by increasing glycosphingolipid levels and reducing cholesterol. Consequently, LXR activation lowered plasma membrane lipid order (stability), and an LXR antagonist could block this effect. LXR stimulation also reduced lipid order at the immune synapse and accelerated activation of proximal T cell signaling molecules. Ultimately, LXR activation dampened proinflammatory T cell function. Finally, compared with responder T cells, regulatory T cells had a distinct pattern of LXR target gene expression corresponding to reduced lipid order. This suggests LXR-driven lipid metabolism could contribute to functional specialization of these T cell subsets. Overall, we report a mode of action for LXR in T cells involving the regulation of glycosphingolipid and cholesterol metabolism and demonstrate its relevance in modulating T cell function.

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LXR alters CD4+ T cell function through direct regulation of glycosphingolipid synthesis

10.1101/721050 ◽

2019 ◽

Cited By ~ 1

Author(s):

Kirsty E Waddington ◽

George A Robinson ◽

Beatriz Rubio-Cuesta ◽

Eden Chrifi-Alaoui ◽

Sara Andreone ◽

...

Keyword(s):

T Cells ◽

Plasma Membrane ◽

Lipid Metabolism ◽

T Cell ◽

T Cell Activation ◽

Cell Function ◽

Cholesterol Metabolism ◽

T Cell Subsets ◽

Lipid Order ◽

T Cell Function

AbstractThe liver X receptor (LXR) is a key transcriptional regulator of cholesterol, fatty acid, and phospholipid metabolism. Dynamic remodeling of immunometabolic pathways, including lipid metabolism, is a crucial step in T cell activation. Here we explored the role of LXR-regulated metabolic processes in primary human CD4+ T cells, and their role in controlling plasma membrane lipids (glycosphingolipids and cholesterol) which strongly influence T cell immune signaling and function. Crucially, we identified the glycosphingolipid biosynthesis enzyme glucosylceramide synthase (UGCG) as a direct transcriptional LXR target. LXR activation by agonist GW3965 or endogenous oxysterol ligands significantly altered the glycosphingolipid:cholesterol balance in the plasma membrane by increasing glycosphingolipid levels and reducing cholesterol. Consequently, LXR activation lowered plasma membrane lipid order (stability), and an LXR antagonist could block this effect. LXR stimulation also reduced lipid order at the immune synapse and accelerated activation of proximal T cell signaling molecules. Ultimately, LXR activation dampened pro-inflammatory T cell function. Finally, compared to responder T cells, regulatory T cells had a distinct pattern of LXR-target gene expression corresponding to reduced lipid order. This suggests LXR-driven lipid metabolism could contribute to functional specialization of these T cell subsets. Overall, we report a novel mode of action for LXR in T cells involving the regulation of glycosphingolipid and cholesterol metabolism, and demonstrate its relevance in modulating T cell function.

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Limited cholesterol depletion causes aggregation of plasma membrane lipid rafts inducing T cell activation

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ◽

10.1016/j.bbalip.2010.02.003 ◽

2010 ◽

Vol 1801 (6) ◽

pp. 625-634 ◽

Cited By ~ 44

Author(s):

Saleemulla Mahammad ◽

Jelena Dinic ◽

Jeremy Adler ◽

Ingela Parmryd

Keyword(s):

Plasma Membrane ◽

T Cell ◽

Lipid Rafts ◽

T Cell Activation ◽

Cell Activation ◽

Membrane Lipid ◽

Cholesterol Depletion ◽

Plasma Membrane Lipid

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Faculty Opinions recommendation of Contamination of nuclear fractions with plasma membrane lipid rafts.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1072051.525027 ◽

2007 ◽

Author(s):

Michael Roth

Keyword(s):

Plasma Membrane ◽

Lipid Rafts ◽

Membrane Lipid ◽

Plasma Membrane Lipid

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1P-0227 Apolipoprotein A-1 interaction with plasma membrane lipid rafts controls cholesterol export from macrophages

Atherosclerosis Supplements ◽

10.1016/s1567-5688(03)90298-4 ◽

2003 ◽

Vol 4 (2) ◽

pp. 69 ◽

Cited By ~ 2

Author(s):

W. Jessup ◽

K. Gaus ◽

L. Kritharides ◽

A. Boettcher ◽

W. Drobnik ◽

...

Keyword(s):

Plasma Membrane ◽

Lipid Rafts ◽

Membrane Lipid ◽

Apolipoprotein A ◽

Plasma Membrane Lipid

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Moderate Static Magnetic Field (6 mT)-Induced Lipid Rafts Rearrangement Increases Silver NPs Uptake in Human Lymphocytes

Molecules ◽

10.3390/molecules25061398 ◽

2020 ◽

Vol 25 (6) ◽

pp. 1398

Author(s):

Cristian Vergallo ◽

Elisa Panzarini ◽

Bernardetta Anna Tenuzzo ◽

Stefania Mariano ◽

Ada Maria Tata ◽

...

Keyword(s):

Plasma Membrane ◽

Lipid Rafts ◽

Lipid Raft ◽

Human Lymphocytes ◽

Peripheral Blood Lymphocytes ◽

Membrane Lipid ◽

Membrane Perturbation ◽

Plasma Membrane Lipid ◽

Silver Nps ◽

Surface Ligand

One of the most relevant drawbacks in medicine is the ability of drugs and/or imaging agents to reach cells. Nanotechnology opened new horizons in drug delivery, and silver nanoparticles (AgNPs) represent a promising delivery vehicle for their adjustable size and shape, high-density surface ligand attachment, etc. AgNPs cellular uptake involves different endocytosis mechanisms, including lipid raft-mediated endocytosis. Since static magnetic fields (SMFs) exposure induces plasma membrane perturbation, including the rearrangement of lipid rafts, we investigated whether SMF could increase the amount of AgNPs able to pass the peripheral blood lymphocytes (PBLs) plasma membrane. To this purpose, the effect of 6-mT SMF exposure on the redistribution of two main lipid raft components (i.e., disialoganglioside GD3, cholesterol) and on AgNPs uptake efficiency was investigated. Results showed that 6 mT SMF: (i) induces a time-dependent GD3 and cholesterol redistribution in plasma membrane lipid rafts and modulates gene expression of ATP-binding cassette transporter A1 (ABCA1), (ii) increases reactive oxygen species (ROS) production and lipid peroxidation, (iii) does not induce cell death and (iv) induces lipid rafts rearrangement, that, in turn, favors the uptake of AgNPs. Thus, it derives that SMF exposure could be exploited to enhance the internalization of NPs-loaded therapeutic or diagnostic molecules.

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Membrane lipid rafts are disturbed in the response of rat skeletal muscle to short-term disuse

AJP Cell Physiology ◽

10.1152/ajpcell.00365.2016 ◽

2017 ◽

Vol 312 (5) ◽

pp. C627-C637 ◽

Cited By ~ 19

Author(s):

Alexey M. Petrov ◽

Violetta V. Kravtsova ◽

Vladimir V. Matchkov ◽

Alexander N. Vasiliev ◽

Andrey L. Zefirov ◽

...

Keyword(s):

Skeletal Muscle ◽

Plasma Membrane ◽

Lipid Rafts ◽

Lipid Raft ◽

Motor Nerve ◽

Membrane Lipid ◽

Hindlimb Suspension ◽

Cholera Toxin B Subunit ◽

Plasma Membrane Lipid ◽

Intracellular Ca

Marked loss of skeletal muscle mass occurs under various conditions of disuse, but the molecular and cellular mechanisms leading to atrophy are not completely understood. We investigate early molecular events that might play a role in skeletal muscle remodeling during mechanical unloading (disuse). The effects of acute (6–12 h) hindlimb suspension on the soleus muscles from adult rats were examined. The integrity of plasma membrane lipid rafts was tested utilizing cholera toxin B subunit or fluorescent sterols. In addition, resting intracellular Ca2+ level was analyzed. Acute disuse disturbed the plasma membrane lipid-ordered phase throughout the sarcolemma and was more pronounced in junctional membrane regions. Ouabain (1 µM), which specifically inhibits the Na-K-ATPase α2 isozyme in rodent skeletal muscles, produced similar lipid raft changes in control muscles but was ineffective in suspended muscles, which showed an initial loss of α2 Na-K-ATPase activity. Lipid rafts were able to recover with cholesterol supplementation, suggesting that disturbance results from cholesterol loss. Repetitive nerve stimulation also restores lipid rafts, specifically in the junctional sarcolemma region. Disuse locally lowered the resting intracellular Ca2+ concentration only near the neuromuscular junction of muscle fibers. Our results provide evidence to suggest that the ordering of lipid rafts strongly depends on motor nerve input and may involve interactions with the α2 Na-K-ATPase. Lipid raft disturbance, accompanied by intracellular Ca2+ dysregulation, is among the earliest remodeling events induced by skeletal muscle disuse.

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