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

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.