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We have investigated the potential role of CD1d-restricted natural killer T (NKT) cells in the development of atherosclerosis in mice. When fed an atherogenic diet (AD), NKT cell-deficient CD1d(-/-) mice had significantly smaller atherosclerotic lesions than AD-fed C57BL/6 (wild-type [WT]) mice. A significant reduction in atherosclerotic lesions was also demonstrated in AD-fed, low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice reconstituted with CD1d(-/-) bone marrow cells compared with the lesions observed in Ldlr(-/-)mice reconstituted with WT marrow cells. In addition, repeated injections of alpha-GalCer or the related glycolipid OCH to apolipoprotein E knockout (apoE(-/-)) mice during the early phase of atherosclerosis significantly enlarged the lesion areas compared with mice injected with vehicle control. However, administering alpha-GalCer to apoE(-/-) mice with established lesions did not significantly increase the lesion area but considerably decreased the collagen content. Atherosclerosis development in either AD-fed WT or apoE(-/-) mice was associated with the presence of Valpha14Jalpha18 transcripts in the atherosclerotic arterial walls, indicating that NKT cells were recruited to these lesions. Thioglycolate-elicited macrophages pulsed with oxidized low-density lipoproteins expressed enhanced CD1d levels and induced NKT cells to produce interferon-gamma, a potentially proatherogenic T-helper 1 (TH1) cytokine. Collectively, we conclude that NKT cells are proatherogenic in mice.

Original publication

DOI

10.1182/blood-2003-10-3485

Type

Journal article

Journal

Blood

Publication Date

10/2004

Volume

104

Pages

2051 - 2059

Addresses

Division of Immunobiology, Research Section of Pathophysiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.

Keywords

Spleen, Leukocytes, Mononuclear, Killer Cells, Natural, T-Lymphocytes, Th1 Cells, Bone Marrow Cells, Animals, Mice, Inbred C57BL, Mice, Transgenic, Mice, Knockout, Mice, Arteriosclerosis, Glycolipids, Apolipoproteins E, RNA, Messenger, Antigens, CD1, Bone Marrow Transplantation, Flow Cytometry, Diet, Atherogenic, Reverse Transcriptase Polymerase Chain Reaction, Transgenes, Time Factors, Interferon-gamma, Antigens, CD1d