SUMMARY The important role of adaptive immunity in cardiovascular disease (CVD) is established. However, much is still unknown regarding how adaptive immunity can be manipulated to benefit CVD outcomes. Atherosclerosis, the most common form of CVD, is characterized by accumulation of lipid and immune cells in the artery wall that leads to plaque formation. Recent single cell RNAseq data in human atherosclerotic confirm that T cells make up a large fraction of the cell population in lesions. T cells are important to the atherosclerotic process as effector T cells (Th1 and Th17) seem to promote plaque growth and instability whereas regulatory T cells (Tregs) are critical for inhibition of atherogenesis and induce regression of established plaques. In humans, Tregs are associated with plaque stability and protection against cardiac events. These data are consistent with mouse models that show Tregs numbers in plaques decrease as atherosclerosis progresses and remaining Tregs Th1-like inflammatory phenotype. Why Tregs dedifferentiate or become dysfunctional in atherosclerosis is not completely understood, but recent studies suggest that oxidized low density lipoprotein (oxLDL) may play a functional role in this process. Preliminary studies from our laboratory examined whether oxidized phospholipid (oxPAPC), associated with atherosclerosis and oxLDL, could affect Treg differentiation, stability, and function. Our preliminary data show that, oxPAPC reduced Treg viability and increased expression of the Th1-associated transcription factor T-bet and production of IFN- thus promoting the Th1-like Treg phenotype. This effect was Treg-specific as cells skewed in Th1 or Th17 conditions were not affected by oxPAPC. These oxPAPC Tregs were also less suppressive in vitro. The effect of oxPAPC on Tregs was partially dependent on CD36 and IFN-. Interestingly, IFN- has been shown to destabilize Tregs in the tumor microenvironment and data in this proposal show that neutralization of IFN- in Treg skewing cultures inhibits expression of T-bet in FoxP3+ cells. Therefore, we hypothesize that oxidized phospholipids associated with atherosclerosis induce an effector- phenotype in Tregs that is partially dependent on IFN-. To test this hypothesis we propose two specific aims. The first will examine the role of CD36/TLR and IFN- signaling on the dysregulation of Tregs in the presence of oxPLs and determine if these Tregs can protect from atherosclerosis in vivo. The second, will examine whether CD36 or responses to IFN- are responsible for destabilization of the Treg compartment during atherosclerosis in vivo. This work will uncover novel information on the role of oxidized phospholipid on Treg dysfunction in atherosclerosis and will provide valuable insight for future clinical interventions.