Cardiovascular Research Advance Access [Accepted Manuscript] published online on January 10, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn005
Deficiency of Invariant V
14 Natural Killer T Cells Decreases Atherosclerosis in LDL Receptor Null Mice
1 Department of Pathology and Laboratory Medicine, University of Ottawa; Ottawa, Canada
2 Department of Cellular and Molecular Medicine, University of Ottawa; Ottawa, Canada
3 Vascular Biology Group, University of Ottawa Heart Institute, Ottawa, Canada
* Corresponding author: Stewart C. Whitman, Ph.D., University of Ottawa Heart Institute, 40 Ruskin St., Room H259A, Ottawa, Ontario, Canada, K1Y 4W7. Telephone: (613) 761-4289; Fax: (613) 761-4237; E-mail: 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
14) NKT cell population protects mice from the disease.
Methods: Targeted deletion of the J18 gene results in selective depletion of CD1d-dependent V14 NKT cells in C57BL/6 mice without affecting the population of other NKT, NK, and conventional T cells. Therefore, to study the effect of V14 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 J18 gene following the feeding of these mice a cholesterol- and fat-enriched diet for 8 weeks.
Results: 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 V14 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)-
was significantly reduced in lesions from J18–/- 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- expression.
KEYWORDS atherosclerosis; cytokines; histo(patho)logy; immunology; leukocytes
Time for primary review: 41
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