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

Suzanne E Engelen, Francesca A Ververs, Angela Markovska, B Christoffer Lagerholm, Jordan M Kraaijenhof, Laura Ie Yousif, Yasemin-Xiomara Zurke, Can Mc Gulersonmez, Sander Kooijman, Michael Goddard, Robert J van Eijkeren, Peter J Jervis, Gurdyal S Besra, Saskia Haitjema, Folkert W Asselbergs, Eric Kalkhoven, Hidde L Ploegh, Marianne Boes, Vincenzo Cerundolo, G Kees HovinghMariolina Salio, Edwin Ca Stigter, Patrick Cn Rensen, Claudia Monaco, Henk S Schipper

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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.

Original languageEnglish
Article numbere158089
JournalJCI Insight
Issue number9
Early online date28 Mar 2023
Publication statusPublished - 8 May 2023


  • Immunology
  • Lipoproteins
  • NKT cells


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