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 Ca
AU - Rensen, Patrick Cn
AU - Monaco, Claudia
AU - Schipper, Henk S
N1 - Funding Information:
The authors are grateful to patients and controls for donating their PBMCs. We thank Uzi Gileadi (MRC Weatherall Institute of Molecular Medicine, Oxford, United Kingdom) for the Cd1d–/– bone marrow and the NIH Tetramer Facility for providing CD1d tetramers. We are grateful to Ewoud Compeer and Nata-cha Zanin (Kennedy Institute, Oxford, United Kingdom) and Ulrike Schulze (MRC Weatherall Institute of Molecular Medicine, Oxford, United Kingdom) for sharing their imaging expertise. Finally, we thank Stan van de Graaf (Amsterdam Gastroenterology & Metabolism Research Institute, Amsterdam, the Netherlands) and Bart van de Sluijs (Center for Liver, Digestive and Metabolic Diseases, Groningen, the Netherlands) for the helpful discussions. This work was supported by a Kennedy Trust Clinical Research Fellowship (SEE), a Dutch Veni-Nederlandse organisatie voor Wetenschappelijk Onderzoek (Dutch Research Council) Innovational Research Incentive (grant number 91618150) and a Marie Curie Individual Fellowship (H2020-MSCA-IF-2017 grant number 797788) (HSS), the Medical Research Council (MC_UU_12009 and MC_UU_12010) and the Wolfson Foundation (BCL), the MRC (MR/S000542/1) (GSB), the Dutch Diabetes Foundation (grant 2014.00.1760) (RJVE), the UCL Hospitals National Institute of Health and Care Research Biomedical Research Centre (FWA), and the Medical Research Council Human Immunology Unit core fund and Cancer Research United Kingdom (Programme Grant C399/A2291) (MS and VC).
Funding Information:
The authors are grateful to patients and controls for donating their PBMCs. We thank Uzi Gileadi (MRC Weatherall Institute of Molecular Medicine, Oxford, United Kingdom) for the Cd1d–/– bone marrow and the NIH Tetramer Facility for providing CD1d tetramers. We are grateful to Ewoud Compeer and Natacha Zanin (Kennedy Institute, Oxford, United Kingdom) and Ulrike Schulze (MRC Weatherall Institute of Molecular Medicine, Oxford, United Kingdom) for sharing their imaging expertise. Finally, we thank Stan van de Graaf (Amsterdam Gastroenterology & Metabolism Research Institute, Amsterdam, the Netherlands) and Bart van de Sluijs (Center for Liver, Digestive and Metabolic Diseases, Groningen, the Netherlands) for the helpful discussions. This work was supported by a Kennedy Trust Clinical Research Fellowship (SEE), a Dutch Veni-Nederlandse organisatie voor Wetenschappelijk Onderzoek (Dutch Research Council) Innovational Research Incentive (grant number 91618150) and a Marie Curie Individual Fellowship (H2020-MSCA-IF-2017 grant number 797788) (HSS), the Medical Research Council (MC_UU_12009 and MC_UU_12010) and the Wolfson Foundation (BCL), the MRC (MR/S000542/1) (GSB), the Dutch Diabetes Foundation (grant 2014.00.1760) (RJVE), the UCL Hospitals National Institute of Health and Care Research Biomedical Research Centre (FWA), and the Medical Research Council Human Immunology Unit core fund and Cancer Research United Kingdom (Programme Grant C399/A2291) (MS and VC).
Publisher Copyright:
© 2023, Engelen et al.
PY - 2023/5/8
Y1 - 2023/5/8
N2 - 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.
AB - 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.
KW - Immunology
KW - Lipoproteins
KW - NKT cells
UR - http://www.scopus.com/inward/record.url?scp=85159549504&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.158089
DO - 10.1172/jci.insight.158089
M3 - Article
C2 - 36976644
SN - 2379-3708
VL - 8
JO - JCI Insight
JF - JCI Insight
IS - 9
M1 - e158089
ER -