Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis
Roland Klingenberg, Norbert Gerdes, Robert M. Badeau, Anton Gisterå, Daniela Strodthoff, Daniel F.J. Ketelhuth, Anna M. Lundberg, Mats Rudling, Stefan K. Nilsson, Gunilla Olivecrona, Stefan Zoller, Christine Lohmann, Thomas F. Lüscher, Matti Jauhiainen, Tim Sparwasser, Göran K. Hansson
Roland Klingenberg, Norbert Gerdes, Robert M. Badeau, Anton Gisterå, Daniela Strodthoff, Daniel F.J. Ketelhuth, Anna M. Lundberg, Mats Rudling, Stefan K. Nilsson, Gunilla Olivecrona, Stefan Zoller, Christine Lohmann, Thomas F. Lüscher, Matti Jauhiainen, Tim Sparwasser, Göran K. Hansson
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Research Article Cardiology

Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis

Abstract

Atherosclerosis is a chronic inflammatory disease promoted by hyperlipidemia. Several studies support FOXP3-positive regulatory T cells (Tregs) as inhibitors of atherosclerosis; however, the mechanism underlying this protection remains elusive. To define the role of FOXP3-expressing Tregs in atherosclerosis, we used the DEREG mouse, which expresses the diphtheria toxin (DT) receptor under control of the Treg-specific Foxp3 promoter, allowing for specific ablation of FOXP3+ Tregs. Lethally irradiated, atherosclerosis-prone, low-density lipoprotein receptor–deficient (Ldlr–/–) mice received DEREG bone marrow and were injected with DT to eliminate FOXP3+ Tregs. Depletion of Tregs caused a 2.1-fold increase in atherosclerosis without a concomitant increase in vascular inflammation. These mice also exhibited a 1.7-fold increase in plasma cholesterol and an atherogenic lipoprotein profile with increased levels of VLDL. Clearance of VLDL and chylomicron remnants was hampered, leading to accumulation of cholesterol-rich particles in the circulation. Functional and protein analyses complemented by gene expression array identified reduced protein expression of sortilin-1 in liver and increased plasma enzyme activity of lipoprotein lipase, hepatic lipase, and phospholipid transfer protein as mediators of the altered lipid phenotype. These results demonstrate that FOXP3+ Tregs inhibit atherosclerosis by modulating lipoprotein metabolism.

Authors

Roland Klingenberg, Norbert Gerdes, Robert M. Badeau, Anton Gisterå, Daniela Strodthoff, Daniel F.J. Ketelhuth, Anna M. Lundberg, Mats Rudling, Stefan K. Nilsson, Gunilla Olivecrona, Stefan Zoller, Christine Lohmann, Thomas F. Lüscher, Matti Jauhiainen, Tim Sparwasser, Göran K. Hansson

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Figure 3

Depletion of Tregs affects cellular composition of atheroma.

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Depletion of Tregs affects cellular composition of atheroma. (A) Represe...
(A) Representative fluorescence micrographs depicting eGFP+FOXP3+ cells (arrowheads) and eGFP–FOXP3+ (arrows) cells in aortic lesions of DEREG/Ldlr–/– mice treated for 8 weeks with PBS or DT. Anti-GFP was labeled with AlexaFluor 488 (green), anti-FOXP3 with AlexaFluor 555 (red), and nuclei with DAPI (blue). (B) Quantitation of immunohistochemical staining for T cells (CD3+), Tregs (FOXP3+), and I-Ab–expressing (MHCII-expressing) cells (all expressed as stained cells per lesion area) in the proximal aorta of chimeric DEREG/Ldlr–/– mice treated for 8 weeks with DT or PBS; n = 7–8 mice per group. (C) Quantitation of immunohistochemical staining for macrophages (CD68+), dendritic cells (CD11c+), and expression of the adhesion molecule VCAM-1 (all expressed as stained area per lesion area) in the aortic sinus of chimeric DEREG/Ldlr–/– mice treated for 8 weeks with DT or PBS; n = 7–8 mice per group. (D) Cellularity of atherosclerotic lesions (DAPI+ nuclei per lesion area) in the proximal aorta of chimeric DEREG/Ldlr–/– mice treated for 8 weeks with PBS or DT; n = 7–8 mice per group. (E) Necrotic core area relative to total atherosclerotic lesion area in the proximal aorta of chimeric DEREG/Ldlr–/– mice treated for 8 weeks with PBS or DT; n = 7–8 mice per group. *P < 0.05; **P < 0.01. Scale bars: 50 μm.