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Cardiovascular Research Advance Access originally published online on January 10, 2008
Cardiovascular Research 2008 78(1):167-174; doi:10.1093/cvr/cvn005
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.

Deficiency of invariant V{alpha}14 natural killer T cells decreases atherosclerosis in LDL receptor null mice

Leah Rogers1, Sarah Burchat2, Jessica Gage2, Mirela Hasu1, Mohamad Thabet2, Lindsay Wilcox2, Tanya A. Ramsamy2 and Stewart C. Whitman1,2,3,*

1 Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada
2 Vascular Biology Group, University of Ottawa Heart Institute, 40 Ruskin St., Room H259A, Ottawa, ON, Canada K1Y 4W7
3 Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada

* Corresponding author. Tel: +1 613 761 4289; fax: +1 613 761 4237. E-mail address: swhitman{at}ottawaheart.ca

Aims: CD1d-restricted natural killer T (NKT) cells function by regulating numerous immune responses during innate and adaptive immunity. Depletion of all populations of CD1d-dependent NKT cells has been shown by several groups to reduce atherosclerosis in two different mouse models of the disease. In this study, we determined if removal of a single (V{alpha}14) NKT cell population protects mice from the disease.

Methods and results: Targeted deletion of the J{alpha}18 gene results in selective depletion of CD1d-dependent V{alpha}14 NKT cells in C57BL/6 mice without affecting the population of other NKT, NK, and conventional T cells. Therefore, to study the effect of V{alpha}14 NKT cell depletion on the progression of atherosclerosis, we examined the extent of lesion formation using paired littermate LDL receptor null mice that were either +/+ or –/– for the J{alpha}18 gene following the feeding of these mice a cholesterol- and fat-enriched diet for 8 weeks. At the end of the study, we found no difference in either serum total- or lipoprotein-cholesterol distributions between groups. However, quantification of atherosclerosis revealed that V{alpha}14 NKT cell deficiency significantly decreased lesion size in the aortic root (20–28%) and arch (28–38%) in both genders of mice. By coupling the techniques of laser capture microdissection with quantitative real-time RT–PCR, we found that expression of the proatherogenic cytokine interferon (IFN)-{gamma} was significantly reduced in lesions from J{alpha}18–/– mice.

Conclusion: This study is the first to identify a specific subpopulation of NKT cells that promotes atherosclerosis via a mechanism appearing to involve IFN-{gamma} expression.

KEYWORDS Atherosclerosis; Cytokines; Histo(patho)logy; Immunology; Leukocytes

Time for primary review: 41 days


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