Quantitative and Qualitative Differences in Proatherogenic NKT Cells in Apolipoprotein E–Deficient Mice

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Abstract
Background— Atherosclerosis is a disease marked by lipid accumulation and inflammation. Recently, atherosclerosis has gained recognition as an autoimmune-type syndrome characterized by increased activation of the innate and acquired immune systems. Natural killer T (NKT) cells have characteristics of both conventional T cells and NK cells and recognize glycolipid antigens presented in association with CD1d molecules on antigen-presenting cells. The capacity of NKT cells to respond to lipid antigens and modulate innate and acquired immunity suggests that they may play a role in atherogenesis. Methods and Results— We examined the role of NKT cells in atherogenesis and how the atherosclerotic environment affects the NKT cell population itself. The data show that CD1d-deficiency in male apolipoprotein E–deficient (apoE0) mice results in reduction in atherosclerosis, and treatment of apoE0 mice with α-galactosylceramide, a potent and specific NKT cell activator, results in a 2-fold increase in atherosclerosis. Interestingly, we demonstrate that α-galactosylceramide–induced interferon-γ responses and numbers of NKT cells in apoE0 mice show age-dependent qualitative and quantitative differences as compared with age-matched wild-type mice. Conclusions— Collectively, these findings reveal that hyperlipidemia and atherosclerosis have significant effects on NKT cell responses and that these cells are proatherogenic. Natural killer T (NKT) cells have characteristics of both T and NK cells and recognize glycolipid antigens. We show that NKT cell–deficiency in male apoE0 mice results in decreased atherosclerosis whereas activation of NKT cells resulted in a 2-fold increase in atherosclerosis. NKT cell numbers and functions are affected by the hyperlipidemia state.