Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 21, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2017394118
Keywords
LXR; CD4(+) T cells; glycosphingolipids; cholesterol; lipid metabolism
Categories
Funding
- British Heart Foundation PhD Studentship [FS/13/59/30649]
- Multiple Sclerosis Society [76]
- Medical Research Council New Investigator Grant [G0801278]
- British Heart Foundation [PG/13/10/30000]
- Academy of Medical Sciences Newton Advanced Fellowship
- Innovative Medicines Initiative, AntiBiopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Risk consortium [115303]
- Arthritis Research UK Fellowships [20085, 18106]
- Lupus United Kingdom
- Rosetrees Trust [M409]
- University College London Hospital Clinical Research and Development Committee [GCT/2008/EJ, F193]
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The liver X receptor (LXR) plays a key role in regulating cholesterol, fatty acid, and phospholipid metabolism in T cells. Activation of LXR alters the balance of glycosphingolipids and cholesterol in the plasma membrane, resulting in decreased lipid order and dampening proinflammatory T cell function. This study highlights the importance of LXR in modulating T cell immune signaling and function through lipid metabolism regulation.
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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