Abstract
Natural killer T (NKT) cells are a distinct subset of lymphocytes that bridge the innate and adaptive immune response and can be divided into type I invariant NKT cells (iNKT) and type II NKT cells. The objective of this study is to examine the effects of NKT cell on lipid metabolism and the initiation and progression of atherosclerosis in LDL receptor deficient (LDLR−/−) mice. Mice were fed an atherogenic diet for 4 or 8 weeks and plasma lipids, lipoproteins, and atherosclerosis were measured. The selective absence of iNKT cells in Jα18−/−LDLR−/− mice led to an increase in plasma cholesterol levels in female mice. Transgenic Vα14tg/LDLR−/− mice with elevated numbers of iNKT cells had increased late atherosclerosis of the innominate artery, though absence of either iNKT cells or all NKT cells and other CD1d expressing cells had varying effects on atherosclerotic lesion burden in the ascending aortic arch and aortic root. These studies not only highlight the potential modulatory role played by NKT cells in atherosclerosis and lipid metabolism, but also raise the possibility that divergent roles may be played by iNKT and CD1d restricted cells such as type II NKT cells or other CD1d expressing cells.
Highlights
Atherosclerosis is characterized by the retention and modification of lipids in the vessel wall, initiating a complex, chronic inflammatory reaction that involves both the innate and adaptive immune systems [1,2,3]
We have investigated the effects of an increase or absence of endogenous invariant NKT cells (iNKT) cells on both lipoprotein metabolism and atherosclerosis by crossing Vα14 transgenic (Vα14tg) mice and Jα18 deficient (Jα18−/−) mice respectively with LDLR−/− mice and feeding the animals an atherogenic Western type diet (WTD)
In the first section we compare the response of mice with varying levels of iNKT cells (LDLR−/−, Vα14tg/LDLR−/−, and Jα18−/−LDLR−/− mice) to WTD feeding and in the second section we compare the response of mice that lack both iNKT cells and type II natural killer T (NKT) cells (CD1d−/−LDLR−/− mice) with mice lacking only iNKT cells (Jα18−/−LDLR−/− mice)
Summary
Atherosclerosis is characterized by the retention and modification of lipids in the vessel wall, initiating a complex, chronic inflammatory reaction that involves both the innate and adaptive immune systems [1,2,3]. There are at least two broad subsets of CD1d restricted NKT cells: those expressing a semi-invariant T-cell receptor (TCR), often referred to as type I or invariant NKT cells (iNKT), which in the mouse express Vα14Jα18 TCR α-chain and Vβ8, -7, or -2 TCR β-chains and NKT cells that express a more diverse set of TCRs and are referred as type II NKT cells [21] Both sets of NKT cells respond rapidly to engagement of their TCRs with lipid-loaded CD1d by producing a complement of Th1 (e.g., INF-γ and IL-2) and Th2 (e.g., IL-4 and IL-10) cytokines. NKT cells can demonstrate granzyme mediated cell lysis typical of NK cells, and CD1d independent activation of NKT cells involving Toll-like receptors has been reported [19] As such, these cells are uniquely positioned as a bridge between the innate and adaptive branches of the immune response
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