title: 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: Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
authors: Roland
authors: R
authors: Klingenberg
authors: Norbert
authors: N
authors: Gerdes
authors: Robert M
authors: RM
authors: Badeau
authors: Anton
authors: A
authors: Gisterå
authors: Daniela
authors: D
authors: Strodthoff
authors: Daniel F J
authors: DF
authors: Ketelhuth
authors: Anna M
authors: AM
authors: Lundberg
authors: Mats
authors: M
authors: Rudling
authors: Stefan K
authors: SK
authors: Nilsson
authors: Gunilla
authors: G
authors: Olivecrona
authors: Stefan
authors: S
authors: Zoller
authors: Christine
authors: C
authors: Lohmann
authors: Thomas F
authors: TF
authors: Lüscher
authors: Matti
authors: M
authors: Jauhiainen
authors: Tim
authors: T
authors: Sparwasser
authors: Göran K
authors: GK
authors: Hansson
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006937:Hypercholesterolemia / Q000097:blood / Q000276:immunology* / Q000473:pathology; D008049:Lipase / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008055:Lipids / Q000097:blood; D008079:Lipoproteins, VLDL / Q000096:biosynthesis; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D049294:Phospholipid Transfer Proteins / Q000097:blood; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D008055:Lipids; D008079:Lipoproteins, VLDL; D049294:Phospholipid Transfer Proteins; D011973:Receptors, LDL; C510091:phospholipid transfer protein, mouse; D008049:Lipase