T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice
Atherosclerosis is a chronic inflammatory disease driven by hypercholesterolemia. During aging, T-cells accumulate cholesterol, which could lead to a pro-inflammatory phenotype. However, the role of cholesterol efflux pathways mediated by ATP-binding cassette A1 and G1 (ABCA1/ABCG1) in T-cell-dependent age-related inflammation and atherosclerosis remains poorly understood. In this study, we generated mice with T-cell-specific Abca1/Abcg1-deficiency on the low-density-lipoprotein-receptor deficient (Ldlr-/-) background. T-cell Abca1/Abcg1-deficiency decreased blood, lymph node, and splenic T-cells, and increased T-cell activation and apoptosis. T-cell Abca1/Abcg1-deficiency induced 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-cell Abca1/Abcg1-deficiency decreased atherosclerosis and aortic inflammation in middle-aged Ldlr-/- mice, accompanied by decreased T-cells in atherosclerotic plaques. We attribute these effects to T-cell apoptosis downstream of T-cell activation. Collectively, T-cell cholesterol efflux pathways are critical for maintaining T-cell numbers, suppress senescence, and induce atherosclerosis in middle-aged Ldlr-/- mice.