T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice

Abstract

AbstractAtherosclerosis is a chronic inflammatory disease driven by hypercholesterolemia. During aging, T cells accumulate cholesterol, potentially affecting inflammation. However, the effect of cholesterol efflux pathways mediated by ATP-binding cassette A1 and G1 (ABCA1/ABCG1) on T cell-dependent age-related inflammation and atherosclerosis remains poorly understood. In this study, we generate mice with T cell-specificAbca1/Abcg1-deficiency on the low-density-lipoprotein-receptor deficient (Ldlr−/−) background. T cellAbca1/Abcg1-deficiency decreases blood, lymph node, and splenic T cells, and increases T cell activation and apoptosis. T cellAbca1/Abcg1-deficiency induces a premature T cell aging phenotype in middle-aged (12–13 months)Ldlr−/−mice, reflected by upregulation of senescence markers. Despite T cell senescence and enhanced T cell activation, T cellAbca1/Abcg1-deficiency decreases atherosclerosis and aortic inflammation in middle-agedLdlr−/−mice, accompanied by decreased T cells in atherosclerotic plaques. We attribute these effects to T cell apoptosis downstream of T cell activation, compromising T cell functionality. Collectively, we show that T cell cholesterol efflux pathways suppress T cell apoptosis and senescence, and induce atherosclerosis in middle-agedLdlr−/−mice.