TY - JOUR
T1 - Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T-cells
AU - Engelen, Suzanne E
AU - Ververs, Francesca A
AU - Markovska, Angela
AU - Lagerholm, B Christoffer
AU - Kraaijenhof, Jordan M
AU - Yousif, Laura Ie
AU - Zurke, Yasemin-Xiomara
AU - Gulersonmez, Can Mc
AU - Kooijman, Sander
AU - Goddard, Michael
AU - van Eijkeren, Robert J
AU - Jervis, Peter J
AU - Besra, Gurdyal S
AU - Haitjema, Saskia
AU - Asselbergs, Folkert W
AU - Kalkhoven, Eric
AU - Ploegh, Hidde L
AU - Boes, Marianne
AU - Cerundolo, Vincenzo
AU - Hovingh, G Kees
AU - Salio, Mariolina
AU - Stigter, Edwin C A
AU - Rensen, Patrick C N
AU - Monaco, Claudia
AU - Schipper, Henk S
PY - 2023/3/28
Y1 - 2023/3/28
N2 - Invariant Natural Killer T (iNKT) cells act at the interface between lipid metabolism and immunity, due to their restriction to lipid antigens presented on CD1d by antigen presenting cells (APC). How foreign lipid antigens are delivered to APC 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, stable complex formation of lipid antigens α-galactosylceramide (αGalCer), Isoglobotrihexosylceramide (iGb3) and OCH, a sphingosine-truncated analogue of αGalCer, with very-low-density (VLDL) and/or low-density (LDL) lipoproteins in vitro and in vivo. We demonstrate LDL receptor (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 novel mechanism of lipid antigen delivery to APCs, and provides further insight in the immunological capacities of circulating lipoproteins.
AB - Invariant Natural Killer T (iNKT) cells act at the interface between lipid metabolism and immunity, due to their restriction to lipid antigens presented on CD1d by antigen presenting cells (APC). How foreign lipid antigens are delivered to APC 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, stable complex formation of lipid antigens α-galactosylceramide (αGalCer), Isoglobotrihexosylceramide (iGb3) and OCH, a sphingosine-truncated analogue of αGalCer, with very-low-density (VLDL) and/or low-density (LDL) lipoproteins in vitro and in vivo. We demonstrate LDL receptor (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 novel mechanism of lipid antigen delivery to APCs, and provides further insight in the immunological capacities of circulating lipoproteins.
U2 - 10.1172/jci.insight.158089
DO - 10.1172/jci.insight.158089
M3 - Article
C2 - 36976644
SN - 2379-3708
JO - JCI Insight
JF - JCI Insight
ER -