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-CharvetGeert van den Bogaart, Marit Westerterp*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Article number3799
Number of pages23
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - 1-Jul-2022

Keywords

  • Animals
  • Apoptosis
  • Atherosclerosis/genetics
  • Biological Transport
  • Immunologic Deficiency Syndromes
  • Inflammation
  • Mice
  • T-Lymphocytes
  • Thymus Gland/abnormalities

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