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

Research output: Contribution to journalArticlepeer-review

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

Original languageEnglish
Article numbere2017394118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number21
DOIs
Published25 May 2021

Bibliographical note

Funding Information: ACKNOWLEDGMENTS. We are grateful to K.R. Steffenson for the provision of the LXR antibody used for chromatin immunoprecipitation and to A. Castrillo and J. Thorne for earlier discussions on LXRE identification in the UGCG gene. K.E.W. was funded by a British Heart Foundation PhD Studentship (FS/13/59/30649) and the Multiple Sclerosis Society (Grant 76). I.P.-T. was funded by a Medical Research Council New Investigator Grant (G0801278), a British Heart Foundation Project Grant (PG/13/10/30000), and an Academy of Medical Sciences Newton Advanced Fellowship. E.C.J. was funded by Innovative Medicines Initiative Joint Grant Agreement No. 115303, as part of the Anti-Biopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Risk consortium; Arthritis Research UK Fellowships (20085 and 18106); Lupus United Kingdom; The Rosetrees Trust (Grant M409); and the University College London Hospital Clinical Research and Development Committee (Project Grant GCT/2008/EJ and Fast Track Grant F193). Publisher Copyright: © 2021 National Academy of Sciences. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

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.

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