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Blood, 1 October 2004, Vol. 104, No. 7, pp. 2051-2059.
Prepublished online as a Blood First Edition Paper on April 27, 2004; DOI 10.1182/blood-2003-10-3485.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Natural killer T cells accelerate atherogenesis in mice
Yukihito Nakai,
Kazuya Iwabuchi,
Satoshi Fujii,
Naoki Ishimori,
Nyambayar Dashtsoodol,
Keiko Watano,
Tetsuya Mishima,
Chikako Iwabuchi,
Shinya Tanaka,
Jelena S. Bezbradica,
Toshinori Nakayama,
Masaru Taniguchi,
Sachiko Miyake,
Takashi Yamamura,
Akira Kitabatake,
Sebastian Joyce,
Luc Van Kaer, and
Kazunori Onoé
From the Division of Immunobiology, Research Section of Pathophysiology, Institute for Genetic Medicine, Hokkaido University, Sapporo; the Department of Cardiovascular Medicine, Graduate School of Medicine, Hokkaido University, Sapporo; the Laboratory of Molecular and Cellular Pathology, Graduate School of Medicine, Hokkaido University, Sapporo; the Department of Immunology, Graduate School of Medicine, Chiba University; the Laboratory of Immune Regulation, Rikagaku Kenkyusho (RIKEN) Institute of Physical and Chemical Research, Research Center for Allergy and Immunology, Yokohama; the Department of Immunology, National Institute of Neuroscience, NCNP, Kodaira, Japan; the Department of Microbiology and Immunology, School of Medicine, Vanderbilt University, Nashville, TN; and The Jackson Laboratory, Bar Harbor, ME.
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  -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 -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 V14J18 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- , a potentially proatherogenic T-helper 1 (TH1) cytokine. Collectively, we conclude that NKT cells are proatherogenic in mice. (Blood. 2004;104:2051-2059)
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