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

• Main Authors: Bazioti, V. (Author), Bianchi, F. (Author), Dabral, D. (Author), de Boer, R. (Author), de Bruin, A. (Author), Flohr-Svendsen, A. (Author), Groenen, A.G (Author), Guilbaud, E. (Author), Halmos, B. (Author), Havinga, R. (Author), Kloosterhuis, N.J (Author), Kohan, A.B (Author), Koster, M.H (Author), La Rose, A.M (Author), Langelaar-Makkinje, M. (Author), Maassen, S. (Author), Marmolejo-Garza, A. (Author), Pranger, A.T (Author), van de Sluis, B. (Author), van den Bogaart, G. (Author), Westerterp, M. (Author), Yvan-Charvet, L. (Author)
• Format: Article
• Language: English
• Published: Nature Research 2022
• Online Access: View Fulltext in Publisher
• ISBN: 20411723 (ISSN)
• DOI: 10.1038/s41467-022-31135-4

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. © 2022, The Author(s).