Atherosclerosis is a chronic inflammatory disease involving both the innate and adaptive immune system that is initiated in response to hyperlipidemia and the retention and modification of lipids within the artery wall. The adaptive immune system has been shown to modulate the extent of atherosclerosis at selected arterial sites and to influence lipid/lipoprotein metabolism. Natural killer T (NKT) cells respond to lipid antigens presented by CD1 molecules on antigen presenting cells. Our results demonstrate that depending upon the presence of other immune cells, NKT cells are pro- or anti-atherogenic and can influence plasma lipids, especially VLDL, and either NKT cells or CD1d repress the specific production of IgM to oxidized lipids by B1 cells. In addition we have shown that the plasma of LDLR-/- mice contain antigen(s) that activate NKT cells in a CD1d dependent manner. In this proposal we will examine the effect of NKT cells and/or CD1d in the liver on lipid/lipoprotein metabolism (aim 1), in the vessel wall on atherosclerosis (aim 2), and on the specific repression of the production of IgM antibodies to oxidized lipids by B1 cells (aim 3). The effect of NKT cells/CD1d on all these processes is expected to contribute to the pro-atherogenic mechanism of NKT cells. A series of in vivo studies in which the level of NKT cells or expression of CD1d is manipulated are proposed along with in vitro studies to further investigate mechanism of action. In addition, we will attempt to identify the antigen in LDL or atherosclerotic plaques that activate NKT cells. These studies will contribute to our understanding of the role of the adaptive immune system and specifically T cells subclasses on lipoprotein homeostasis and atherosclerosis and will provide evidence for endogenous lipid antigens that stimulate iNKT cells.

Public Health Relevance

The goal of these studies is to understand how iNKT cells, which respond to lipid antigens, influence lipoprotein metabolism and atherosclerosis. These studies will further our understanding of the role of the immune system in the chronic inflammation associated with atherosclerosis and provide an important link between hyperlipidemia and the development of atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088420-02
Application #
7622124
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Kirby, Ruth
Project Start
2008-05-15
Project End
2012-02-29
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
2
Fiscal Year
2009
Total Cost
$383,750
Indirect Cost
Name
University of Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Getz, Godfrey S; Reardon, Catherine A (2017) Natural killer T cells in atherosclerosis. Nat Rev Cardiol 14:304-314
Getz, Godfrey S; Reardon, Catherine A (2016) Do the Apoe-/- and Ldlr-/- Mice Yield the Same Insight on Atherogenesis? Arterioscler Thromb Vasc Biol 36:1734-41
Subramanian, Savitha; Turner, Michael S; Ding, Yilei et al. (2013) Increased levels of invariant natural killer T lymphocytes worsen metabolic abnormalities and atherosclerosis in obese mice. J Lipid Res 54:2831-41
Getz, Godfrey S; Reardon, Catherine A (2012) Animal models of atherosclerosis. Arterioscler Thromb Vasc Biol 32:1104-15
Getz, G S; Vanderlaan, P A; Reardon, C A (2011) Natural killer T cells in lipoprotein metabolism and atherosclerosis. Thromb Haemost 106:814-9