Deficiency of invariant Vα14 natural killer T cells decreases atherosclerosis in LDL receptor null mice

Rogers, Leah
Burchat, Sarah
Gage, Jessica
Hasu, Mirela
Thabet, Mohamad
Wilcox, Lindsay
Ramsamy, Tanya A.
Whitman, Stewart C.

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

Cardiovascular Research 78(1):p 167-174, April 1, 2008.

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 (Vα14) NKT cell population protects mice from the disease.

Methods and results

Targeted deletion of the Jα18 gene results in selective depletion of CD1d-dependent Vα14 NKT cells in C57BL/6 mice without affecting the population of other NKT, NK, and conventional T cells. Therefore, to study the effect of Vα14 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 Jα18 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 Vα14 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)-γ was significantly reduced in lesions from Jα18^−/− 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-γ expression.