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Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T cells

Engelen, SE; Ververs, FA; Markovska, A; Lagerholm, BC; Kraaijenhof, JM; Yousif, LI; Zurke, YX; ... Schipper, HS; + view all (2023) Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T cells. JCI Insight , 8 (9) , Article e158089. 10.1172/jci.insight.158089. Green open access

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Abstract

Invariant natural killer T (iNKT) cells act at the interface between lipid metabolism and immunity because of their restriction to lipid antigens presented on CD1d by antigen-presenting cells (APCs). How foreign lipid antigens are delivered to APCs remains elusive. Since lipoproteins routinely bind glycosylceramides structurally similar to lipid antigens, we hypothesized that circulating lipoproteins form complexes with foreign lipid antigens. In this study, we used 2-color fluorescence correlation spectroscopy to show, for the first time to our knowledge, stable complex formation of lipid antigens α-galactosylceramide (αGalCer), isoglobotrihexosylceramide, and OCH, a sphingosine-truncated analog of αGalCer, with VLDL and/or LDL in vitro and in vivo. We demonstrate LDL receptor-mediated (LDLR-mediated) uptake of lipoprotein-αGalCer complexes by APCs, leading to potent complex-mediated activation of iNKT cells in vitro and in vivo. Finally, LDLR-mutant PBMCs of patients with familial hypercholesterolemia showed impaired activation and proliferation of iNKT cells upon stimulation, underscoring the relevance of lipoproteins as a lipid antigen delivery system in humans. Taken together, circulating lipoproteins form complexes with lipid antigens to facilitate their transport and uptake by APCs, leading to enhanced iNKT cell activation. This study thereby reveals a potentially novel mechanism of lipid antigen delivery to APCs and provides further insight into the immunological capacities of circulating lipoproteins.

Type: Article
Title: Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T cells
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1172/jci.insight.158089
Publisher version: https://doi.org/10.1172/jci.insight.158089
Language: English
Additional information: Copyright: © 2023, Engelen et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
Keywords: Immunology, Lipoproteins, NKT cells, Humans, Natural Killer T-Cells, Antigen-Presenting Cells, Lipoproteins
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics > Clinical Epidemiology
URI: https://discovery.ucl.ac.uk/id/eprint/10171570
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