New Key Publication: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, 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.

Authors:

• 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

Read more: Nature Communications: https://www.nature.com/articles/s41467-022-31135-4