Transient Role for CD1d-Restricted Natural Killer T Cells in the Formation of Atherosclerotic Lesions

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Abstract
Objective— CD1d-restricted natural killer T (NKT) cells are reported to play a proatherogenic role in the development of atherosclerosis. However, the contribution of NKT cells to mature lesion formation and the effector mechanisms through which they act are unknown. Methods and Results— We measured lesion size in CD1d-null (CD1d−/−) mice on the low-density lipoprotein (LDL) receptor–deficient (LDLR−/−) genetic background after 4, 8, and 12 weeks of feeding on a Western diet. Lesions in CD1d−/−LDLR−/− mice were 47% smaller at 4 weeks than CD1d+/+LDLR−/− controls; however, there were no differences in lesion size between CD1d−/−LDLR−/− and CD1d+/+LDLR−/− mice at 8 or 12 weeks. We found that although NKT cells were present in the aortic arch of CD1d+/+LDLR−/− mice on the Western diet, no differences in mRNA abundance for Th1 or Th2 cytokines were observed between CD1d−/−LDLR−/− and CD1d+/+LDLR−/− mice. Conclusions— CD1d-restricted NKT cells contribute to the formation of fatty streaks; however, their influence on lesion progression is transient, and they do not significantly affect the inflammatory cytokine milieu of mature lesions. Mice deficient in CD1d-restricted natural killer T cells have reduced atherosclerosis only during the earliest stages of fatty streak formation, indicating that the contribution of natural killer T cells to lesion formation is transient.