T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice
Venetia Bazioti, Anouk M. La Rose, Sjors Maassen, Frans Bianchi, Rinse de Boer, Benedek Halmos, Deepti Dabral, Emma Guilbaud, Arthur Flohr-Svendsen, Anouk G. Groenen, Alejandro Marmolejo-Garza, Mirjam H. Koster, Niels J. Kloosterhuis, Rick Havinga, Alle T. Pranger, Miriam Langelaar-Makkinje, Alain de Bruin, Bart van de Sluis, Alison B. Kohan, Laurent Yvan-Charvet, Geert van den Bogaart & Marit Westerterp
Atherosclerosis 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-specific Abca1/Abcg1-deficiency on the low-density-lipoprotein-receptor deficient (Ldlr−/−) background. T cell Abca1/Abcg1-deficiency decreases blood, lymph node, and splenic T cells, and increases T cell activation and apoptosis. T cell Abca1/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 cell Abca1/Abcg1-deficiency decreases 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, compromising T cell functionality. Collectively, we show that T cell cholesterol efflux pathways suppress T cell apoptosis and senescence, and induce atherosclerosis in middle-aged Ldlr−/− mice.
T cell, Atherosclerosis, apoptosis