Diet-induced dyslipidemia induces metabolic and migratory adaptations in regulatory T cells

AIMS A hallmark of advanced atherosclerosis is inadequate immunosuppression by regulatory T (Treg) cells inside atherosclerotic lesions. Dyslipidemia has been suggested to alter Treg cell migration by affecting the expression of specific membrane proteins, thereby decreasing Treg cell migration towards atherosclerotic lesions. Besides membrane proteins, cellular metabolism has been shown to be a crucial factor in Treg cell migration. We aimed to determine whether dyslipidemia contributes to altered migration of Treg cells, in part, by affecting cellular metabolism. METHODS AND RESULTS Dyslipidemia was induced by feeding Ldlr-/- mice a Western-type diet for 16-20 weeks and intrinsic changes in Treg cells affecting their migration and metabolism were examined. Dyslipidemia was associated with altered mTORC2 signaling in Treg cells, decreased expression of membrane proteins involved in migration, including CD62L, CCR7 and S1Pr1, and decreased Treg cell migration towards lymph nodes. Furthermore, we discovered that diet-induced dyslipidemia inhibited mTORC1 signaling, induced PPARδ activation and increased fatty acid (FA) oxidation in Treg cells. Moreover, mass-spectrometry analysis of serum from Ldlr-/- mice with normolipidemia or dyslipidemia showed increases in multiple PPARδ ligands during dyslipidemia. Treatment with a synthetic PPARδ agonist increased the migratory capacity of Treg cells in vitro and in vivo in an FA oxidation dependent manner. Furthermore, diet-induced dyslipidemia actually enhanced Treg cell migration into the inflamed peritoneum and into atherosclerotic lesions in vitro. CONCLUSIONS Altogether, our findings implicate that dyslipidemia does not contribute to atherosclerosis by impairing Treg cell migration as dyslipidemia associated with an effector-like migratory phenotype in Treg cells. TRANSLATIONAL PERSPECTIVE Dyslipidemia, in the form of hypercholesterolemia and hypertriglyceridemia, is a driver of atherosclerosis and cardiovascular disease (CVD). Hence, lipid-lowering therapy is a cornerstone in the treatment of CVD. In the past years, the clinical feasibility of immunotherapy to treat CVD has also been established. As regulatory T (Treg) cells are specialized in immunosuppression, these cells represent a promising target for additional immunotherapies. The presented study suggests that dyslipidemia affects the metabolism of Treg cells and their migration towards sites of inflammation such as atherosclerotic lesions, suggesting that lipid-lowering therapy and metabolic immunotherapy might affect Treg cells through previously unidentified mechanisms.