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

Author:

Waddington Kirsty E.ORCID,Robinson George A.ORCID,Rubio-Cuesta BeatrizORCID,Chrifi-Alaoui Eden,Andreone Sara,Poon Kok-SiongORCID,Ivanova Iveta,Martin-Gutierrez Lucia,Owen Dylan M.,Jury Elizabeth C.ORCID,Pineda-Torra InésORCID

Abstract

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.

Funder

British Heart Foundation

Multiple Sclerosis Society

RCUK | Medical Research Council

Academy of Medical Sciences

Arthritis Research UK

The Rosetrees Trust

University College London Hospital Clinical Research and Development Committee project grant

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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