PT  - JOURNAL ARTICLE
AU  - Kirsty E Waddington
AU  - George A Robinson
AU  - Marsilio Adriani
AU  - Beatriz Rubio-Cuesta
AU  - Eden Chrifi-Alaoui
AU  - Sara Andreone
AU  - Kok-Siong Poon
AU  - Iveta Ivanova
AU  - Lucia Martin-Gutierrez
AU  - Dylan M Owen
AU  - Petra Nytrova
AU  - Eva Kubala Havrdova
AU  - Rachel Farrell
AU  - Elizabeth C Jury
AU  - Inés Pineda-Torra
TI  - Activation of the liver X receptors alters CD4<sup>+</sup> T cell membrane lipids and signalling through direct regulation of glycosphingolipid synthesis
AID  - 10.1101/721050
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 721050
4099  - http://biorxiv.org/content/early/2019/08/23/721050.short
4100  - http://biorxiv.org/content/early/2019/08/23/721050.full
AB  - Liver X Receptors (LXRs) are important transcriptional regulators of intracellular cholesterol, fatty acid, and phospholipid levels. LXRs can dampen inflammation in macrophages by promoting cholesterol efflux and altering plasma membrane lipid rafts; microdomains enriched for cholesterol and glycosphingolipids that regulate immune-cell signalling. However, little is known about the impact of LXR activators on T cell plasma membrane lipid rafts, which are critical for T-cell antigen receptor (TCR) signalling. Here we show that the LXR synthetic agonist GW3965 significantly increases glycosphingolipid levels and reduces cholesterol and lipid order (stability) in the plasma membrane of human CD4+ T cells. Moreover, the GSL biosynthesis enzyme UGCG was identified as a novel direct target of LXR activation. Importantly, LXR-mediated changes in T cell lipid composition were associated with altered spatiotemporal distribution of lipids and signalling molecules at the immune synapse. Crucially, LXR activation altered the kinetics of proximal TCR-signalling events in activated T cells, reduced T cell proliferation and enhanced the production of IL-2 and IL-4. Thus, LXR activation influences T cell function via alteration of the plasma membrane lipid profile. Finally, the expression of UGCG and other LXR-regulated genes and lipids was significantly dysregulated in T-cells isolated from people with multiple sclerosis. Overall, a novel action of LXR has been characterised that involves modulation of lipid raft-associated cholesterol and glycosphingolipids in CD4+ T-cells, which could be of therapeutic relevance in multiple sclerosis.