T regulatory lymphocytes (Treg) maintain immune tolerance by suppressing both innate and adaptive immune cells. Tregs are atheroprotective, yet Treg phenotypes and function are disturbed during atherosclerosis progression. High-density lipoproteins (HDL) are atheroprotective, in large part due to their function in reverse cholesterol transport. However, HDL also performs cholesterol-independent functions, including the transport of sphingosine-1-phosphate (S1P), an important lipid mediator of immunity. Apolipoprotein M, found on HDL, binds S1P to aid in delivery of S1P to cells in the vasculature, including cells involved in adaptive immunity. Based upon our work and that of others, S1P most likely acts to impart differential effects on cytokine production by dendritic cells and lymphocyte depending on the microenvironment. We hypothesize that a novel function of HDL in adaptive immunity is related to the ability of HDL to stabilize Treg homeostasis and suppressive activity in vivo during atherogenesis. We will test our hypotheses in 2 specific aims.
Specific Aim 1 will test the hypothesis that HDL regulates Treg homeostasis in atherosclerosis through S1P action.
Specific Aim 2 will identify mechanisms for how HDL-S1P impacts both cell-autonomous dendritic cell and Treg actions to preserve Treg function in atherosclerosis.

Public Health Relevance

T regulatory lymphocytes (Treg) suppress both innate and adaptive immune cells, and are atheroprotective. High-density lipoproteins (HDL) transport sphingosine-1- phosphate (S1P) in circulation. S1P is an important lipid mediator in immunity. We hypothesize that HDL, through delivery of S1P to immune cells, plays a novel role in adaptive immunity through preservation of Treg homeostasis and suppressive activity in vivo during atherogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL112276-01A1
Application #
8441858
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Liu, Lijuan
Project Start
2013-06-01
Project End
2017-04-30
Budget Start
2013-06-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$707,427
Indirect Cost
$222,483
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Gao, Mingming; Zhao, Dong; Schouteden, Sarah et al. (2014) Regulation of high-density lipoprotein on hematopoietic stem/progenitor cells in atherosclerosis requires scavenger receptor type BI expression. Arterioscler Thromb Vasc Biol 34:1900-9