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

Area of Science:

• Immunometabolism
• Cellular lipidomics
• T cell biology

Background:

• Liver X receptor (LXR) is a critical regulator of lipid metabolism.
• Lipid metabolism remodeling is essential for T cell activation and function.
• Plasma membrane lipid composition influences T cell signaling and immune responses.

Purpose of the Study:

• To investigate the role of LXR-regulated metabolic processes in human CD4+ T cells.
• To determine how LXR affects plasma membrane lipids, including glycosphingolipids and cholesterol.
• To elucidate the impact of LXR on T cell immune signaling and function.

Main Methods:

• Analysis of LXR target genes in primary human CD4+ T cells.
• Assessment of plasma membrane lipid composition (glycosphingolipids, cholesterol) upon LXR activation.
• Measurement of plasma membrane lipid order and T cell signaling molecule activation.
• Comparison of LXR target gene expression in responder versus regulatory T cells.

Main Results:

• Glucosylceramide synthase identified as a direct LXR transcriptional target.
• LXR activation increased glycosphingolipid levels and decreased cholesterol in the plasma membrane.
• LXR activation reduced plasma membrane and immune synapse lipid order, accelerating T cell signaling.
• LXR activation suppressed pro-inflammatory T cell function.
• Distinct LXR target gene expression patterns observed between T cell subsets, correlating with lipid order.

Conclusions:

• LXR modulates T cell function by regulating glycosphingolipid and cholesterol metabolism.
• LXR activation alters plasma membrane lipid homeostasis, impacting T cell signaling and activation.
• LXR-driven lipid metabolism may contribute to the functional specialization of T cell subsets, such as regulatory T cells.