Oxidized phospholipid oxPAPC induces a dysfunctional Th1-like phenotype in regulatory T cells

Regulatory T cells (T_regs) are protective in atherosclerosis but numbers are reduced during disease progression due to cell death and loss of stability. Oxidized lipids are abundant in atherosclerotic lesions and can activate innate immune cells, but there is limited information regarding their impact on T cells. Given the T_reg loss observed during atherosclerosis progression and increase in oxidized lipid levels in the microenvironment, we sought to determine whether an oxidized phospholipid associated with atherosclerosis, oxidized 1-palmitoyl-2-arachidonoylsn-glycero-3-phosphocholine (oxPAPC), alters T_reg differentiation and function. In vitro skews of naïve T cells showed that oxPAPC-treated T_regs were less viable with a greater proportion expressing the Th1 markers T-bet, CXCR3, and IFN-γ. Th1 and Th17 skewed cultures were unaltered by oxPAPC suggesting a T_reg specific effect of oxPAPC. OxPAPC-treated T_regs were less suppressive in vitro and were insufficient to inhibit atherosclerosis progression in an adoptive transfer in  Ldlr^-/- mice fed Western diet for up to 16 weeks. A role for IFN-γ signaling in T_reg dysregulation was examined using T_reg specific IFNγR1 deficient mice. IFNγR1 deficient CD4⁺ T cells skewed in the presence of oxPAPC did not adopt the Th1-like T_reg phenotype compared to control oxPAPC-treated T_regs, indicating that IFNγR signaling was important for oxPAPC-mediated T_reg dysregulation. Bone marrow transplant of Ldlr^-/- showed that T_reg IFNγR1 signaling was atherogenic in males but protective in females. Overall, our findings demonstrate that oxidized phospholipids directly impact T_reg differentiation and decrease their atheroprotective potential.