Atherosclerosis is the major cause of cardiovascular disease, which is the leading cause of death in the western world. Atherosclerotic plaques are found in the arterial wall and consist of lipids and immune cells. T lymphocytes have been shown to play an active role in atherosclerosis. Regulatory T cells (Tregs) are a subset of T cells that express FoxP3 and suppress autoimmunity. Tregs have been reported to be antiatherogenic. TH17 cells are a subset of T cells that express ROR3t and secrete IL-17 that are implicated in promoting autoimmunity but their role in atherosclerosis is controversial. Tregs and Th17 cells have an intimate developmental relationship and Tregs have been shown to be able to convert to TH17 cells with the appropriate stimuli. ABCG1 is an ATP-binding cassette transporter that participates in reverse cholesterol transport by transferring excess cholesterol from peripheral cells to HDL. Mice that lack ABCG1 in hematopoietic cells are protected from developing severe atherosclerosis. The mechanism that confers this atheroprotection is currently unknown. We have preliminary data that there is increased ROR3t expression in Tregs from ApoE-/- mice fed an atherogenic diet;however ROR3T expression is not increased in ApoE-/- ABCG1-/- mice fed the same diet. ROR3t is the master regulator of TH17 cells and an increase in its expression may indicate a shift from antiatherogenic Tregs to TH17 cells during early atherogenesis. We also have data that there is a marked reduction in IL-17 production by T cells in ApoE-/-ABCG1-/- mice fed western diet. We hypothesize that absence of ABCG1 in CD4 T cells is atheroprotective due to impaired TH17 differentiation. This proposal will study the role of ABCG1 on CD4+ T cell function during atherosclerosis progression in the following specific aims.
Specific Aim 1 will test the hypothesis that absence of ABCG1 in CD4+ T cells inhibits TH17 differentiation. We have preliminary data showing that ABCG1 deficiency greatly reduces the differentiation of TH17 cells. We will investigate the mechanisms involved in this phenomenon.
Specific Aim 2 will test the hypothesis that absence of ABCG1 in CD4+ T cells is atheroprotective. We will produce a CD4+ T cell specific deletion of ABCG1 in atherosclerosis prone mice by crossing ABCG1fl/flApoE-/- mice with CD4-Cre mice. These mice will be put on an atherogenic diet for 8 or 20 weeks to investigate early and advanced atherosclerosis respectively. Atherosclerosis severity will then be measured. The numbers of TH1, TH2, Tregs and TH17 cells present in the aortic walls and spleens of the mice during atherosclerosis progression using flow cytometry. The role of ABCG1 in CD4+ T cells, particularly it's role in Tregs and TH17 cells, may be important in promoting atherosclerosis progression. This study may clarify the currently controversial roles of ABCG1 and TH17 cells in atherosclerosis and help determine their potential as therapeutic targets of this disease.
Atherosclerosis is the major cause of cardiovascular disease, which is the leading cause of death in the western world. My proposal investigates how cholesterol modulates immune cell function in atherosclerosis progression.
|Cheng, Hsin-Yuan; Gaddis, Dalia E; Wu, Runpei et al. (2016) Loss of ABCG1 influences regulatory T cell differentiation and atherosclerosis. J Clin Invest 126:3236-46|
|Haynes, LaTeira D; Verma, Shilpi; McDonald, Bryan et al. (2015) Cardif (MAVS) Regulates the Maturation of NK Cells. J Immunol 195:2157-67|