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

Venetia Bazioti, Anouk M. Rose, Sjors Maassen, Frans Bianchi, Rinse 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 Bruin, Bart Sluis, Alison B. Kohan, Laurent Yvan-Charvet, Geert Bogaart and Marit Westerterp ()
Additional contact information
Venetia Bazioti: University Medical Center Groningen, University of Groningen
Anouk M. Rose: University Medical Center Groningen, University of Groningen
Sjors Maassen: University of Groningen
Frans Bianchi: University of Groningen
Rinse Boer: University of Groningen
Benedek Halmos: University Medical Center Groningen, University of Groningen
Deepti Dabral: University of Groningen
Emma Guilbaud: Fédération Hospitalo-Universitaire (FHU) Oncoage
Arthur Flohr-Svendsen: University Medical Center Groningen, University of Groningen
Anouk G. Groenen: University Medical Center Groningen, University of Groningen
Alejandro Marmolejo-Garza: University Medical Center Groningen, University of Groningen
Mirjam H. Koster: University Medical Center Groningen, University of Groningen
Niels J. Kloosterhuis: University Medical Center Groningen, University of Groningen
Rick Havinga: University Medical Center Groningen, University of Groningen
Alle T. Pranger: University Medical Center Groningen, University of Groningen
Miriam Langelaar-Makkinje: University Medical Center Groningen, University of Groningen
Alain Bruin: University Medical Center Groningen, University of Groningen
Bart Sluis: University Medical Center Groningen, University of Groningen
Alison B. Kohan: University of Pittsburgh
Laurent Yvan-Charvet: Fédération Hospitalo-Universitaire (FHU) Oncoage
Geert Bogaart: University of Groningen
Marit Westerterp: University Medical Center Groningen, University of Groningen

Nature Communications, 2022, vol. 13, issue 1, 1-23

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-31135-4

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