Activation of the Regulatory T-Cell/Indoleamine 2,3-Dioxygenase Axis Reduces Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice
T-cell activation is characteristic during the development of atherosclerosis. While overall T-cell responses have been implicated in disease acceleration, regulatory T cells (Tregs) exhibit atheroprotective effects. The expression of the enzyme indoleamine 2,3-dioxygenase-1 (IDO1), which catalyzes...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2018.00950/full |
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| author | Maria J. Forteza Konstantinos A. Polyzos Roland Baumgartner Bianca E. Suur Bianca E. Suur Marion Mussbacher Daniel K. Johansson Andreas Hermansson Göran K. Hansson Daniel F. J. Ketelhuth |
| author_facet | Maria J. Forteza Konstantinos A. Polyzos Roland Baumgartner Bianca E. Suur Bianca E. Suur Marion Mussbacher Daniel K. Johansson Andreas Hermansson Göran K. Hansson Daniel F. J. Ketelhuth |
| author_sort | Maria J. Forteza |
| collection | DOAJ |
| description | T-cell activation is characteristic during the development of atherosclerosis. While overall T-cell responses have been implicated in disease acceleration, regulatory T cells (Tregs) exhibit atheroprotective effects. The expression of the enzyme indoleamine 2,3-dioxygenase-1 (IDO1), which catalyzes the degradation of tryptophan (Trp) along the kynurenine pathway, has been implicated in the induction and expansion of Treg populations. Hence, Tregs can reciprocally promote IDO1 expression in dendritic cells (DCs) via reverse signaling mechanisms during antigen presentation. In this study, we hypothesize that triggering the “Treg/IDO axis” in the artery wall is atheroprotective. We show that apolipoprotein B100-pulsed tumor growth factor beta 2-treated tolerogenic DCs promote de novo FoxP3+ Treg expansion in vivo. This local increase in Treg numbers is associated with increased vascular IDO1 expression and a robust reduction in the atherosclerotic burden. Using human primary cell cultures, we show for the first time that IDO1 expression and activity can be regulated by cytotoxic T-lymphocyte associated protein-4, which is a constitutive molecule expressed and secreted by Tregs, in smooth muscle cells, endothelial cells, and macrophages. Altogether, our data suggest that Tregs and IDO1-mediated Trp metabolism can mutually regulate one another in the vessel wall to promote vascular tolerance mechanisms that limit inflammation and atherosclerosis. |
| first_indexed | 2024-12-17T02:34:58Z |
| format | Article |
| id | doaj.art-8ea87542973648e4934b564803e98872 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-17T02:34:58Z |
| publishDate | 2018-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-8ea87542973648e4934b564803e988722022-12-21T22:06:53ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-05-01910.3389/fimmu.2018.00950372247Activation of the Regulatory T-Cell/Indoleamine 2,3-Dioxygenase Axis Reduces Vascular Inflammation and Atherosclerosis in Hyperlipidemic MiceMaria J. Forteza0Konstantinos A. Polyzos1Roland Baumgartner2Bianca E. Suur3Bianca E. Suur4Marion Mussbacher5Daniel K. Johansson6Andreas Hermansson7Göran K. Hansson8Daniel F. J. Ketelhuth9Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, SwedenCardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, SwedenCardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, SwedenCenter for Molecular Medicine, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, SwedenDepartment of Vascular Surgery, Karolinska University Hospital, Stockholm, SwedenDepartment of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, AustriaCardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, SwedenCardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, SwedenCardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, SwedenCardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, SwedenT-cell activation is characteristic during the development of atherosclerosis. While overall T-cell responses have been implicated in disease acceleration, regulatory T cells (Tregs) exhibit atheroprotective effects. The expression of the enzyme indoleamine 2,3-dioxygenase-1 (IDO1), which catalyzes the degradation of tryptophan (Trp) along the kynurenine pathway, has been implicated in the induction and expansion of Treg populations. Hence, Tregs can reciprocally promote IDO1 expression in dendritic cells (DCs) via reverse signaling mechanisms during antigen presentation. In this study, we hypothesize that triggering the “Treg/IDO axis” in the artery wall is atheroprotective. We show that apolipoprotein B100-pulsed tumor growth factor beta 2-treated tolerogenic DCs promote de novo FoxP3+ Treg expansion in vivo. This local increase in Treg numbers is associated with increased vascular IDO1 expression and a robust reduction in the atherosclerotic burden. Using human primary cell cultures, we show for the first time that IDO1 expression and activity can be regulated by cytotoxic T-lymphocyte associated protein-4, which is a constitutive molecule expressed and secreted by Tregs, in smooth muscle cells, endothelial cells, and macrophages. Altogether, our data suggest that Tregs and IDO1-mediated Trp metabolism can mutually regulate one another in the vessel wall to promote vascular tolerance mechanisms that limit inflammation and atherosclerosis.http://journal.frontiersin.org/article/10.3389/fimmu.2018.00950/fullatherosclerosisT-cellregulatory T cellIDOtryptophankynurenine |
| spellingShingle | Maria J. Forteza Konstantinos A. Polyzos Roland Baumgartner Bianca E. Suur Bianca E. Suur Marion Mussbacher Daniel K. Johansson Andreas Hermansson Göran K. Hansson Daniel F. J. Ketelhuth Activation of the Regulatory T-Cell/Indoleamine 2,3-Dioxygenase Axis Reduces Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice Frontiers in Immunology atherosclerosis T-cell regulatory T cell IDO tryptophan kynurenine |
| title | Activation of the Regulatory T-Cell/Indoleamine 2,3-Dioxygenase Axis Reduces Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice |
| title_full | Activation of the Regulatory T-Cell/Indoleamine 2,3-Dioxygenase Axis Reduces Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice |
| title_fullStr | Activation of the Regulatory T-Cell/Indoleamine 2,3-Dioxygenase Axis Reduces Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice |
| title_full_unstemmed | Activation of the Regulatory T-Cell/Indoleamine 2,3-Dioxygenase Axis Reduces Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice |
| title_short | Activation of the Regulatory T-Cell/Indoleamine 2,3-Dioxygenase Axis Reduces Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice |
| title_sort | activation of the regulatory t cell indoleamine 2 3 dioxygenase axis reduces vascular inflammation and atherosclerosis in hyperlipidemic mice |
| topic | atherosclerosis T-cell regulatory T cell IDO tryptophan kynurenine |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2018.00950/full |
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