Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T cells
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...
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| Format: | Članak |
| Jezik: | English |
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American Society for Clinical investigation
2023-05-01
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| Serija: | JCI Insight |
| Teme: | |
| Online pristup: | https://doi.org/10.1172/jci.insight.158089 |
| _version_ | 1827767962594967552 |
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| author | Suzanne E. Engelen Francesca A. Ververs Angela Markovska B. Christoffer Lagerholm Jordan M. Kraaijenhof Laura I.E. Yousif Yasemin-Xiomara Zurke Can M.C. 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.K. Hovingh Mariolina Salio Edwin C.A. Stigter Patrick C.N. Rensen Claudia Monaco Henk S. Schipper |
| author_facet | Suzanne E. Engelen Francesca A. Ververs Angela Markovska B. Christoffer Lagerholm Jordan M. Kraaijenhof Laura I.E. Yousif Yasemin-Xiomara Zurke Can M.C. 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.K. Hovingh Mariolina Salio Edwin C.A. Stigter Patrick C.N. Rensen Claudia Monaco Henk S. Schipper |
| author_sort | Suzanne E. Engelen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:05:47Z |
| format | Article |
| id | doaj.art-8fb8c477cbe54ae48780c91ea0abd92d |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:05:47Z |
| publishDate | 2023-05-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-8fb8c477cbe54ae48780c91ea0abd92d2023-11-07T16:25:35ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-05-0189Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T cellsSuzanne E. EngelenFrancesca A. VerversAngela MarkovskaB. Christoffer LagerholmJordan M. KraaijenhofLaura I.E. YousifYasemin-Xiomara ZurkeCan M.C. GulersonmezSander KooijmanMichael GoddardRobert J. van EijkerenPeter J. JervisGurdyal S. BesraSaskia HaitjemaFolkert W. AsselbergsEric KalkhovenHidde L. PloeghMarianne BoesVincenzo CerundoloG.K. HovinghMariolina SalioEdwin C.A. StigterPatrick C.N. RensenClaudia MonacoHenk S. SchipperInvariant 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.https://doi.org/10.1172/jci.insight.158089Immunology |
| spellingShingle | Suzanne E. Engelen Francesca A. Ververs Angela Markovska B. Christoffer Lagerholm Jordan M. Kraaijenhof Laura I.E. Yousif Yasemin-Xiomara Zurke Can M.C. 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.K. Hovingh Mariolina Salio Edwin C.A. Stigter Patrick C.N. Rensen Claudia Monaco Henk S. Schipper Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T cells JCI Insight Immunology |
| title | Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T cells |
| title_full | Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T cells |
| title_fullStr | Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T cells |
| title_full_unstemmed | Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T cells |
| title_short | Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T cells |
| title_sort | lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer t cells |
| topic | Immunology |
| url | https://doi.org/10.1172/jci.insight.158089 |
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