TCR-dependent CD8+ T cell responses drive atherosclerotic plaque instability 2443

Abstract Description Atherosclerosis is a chronic inflammatory condition of the arterial vasculature. The rupture of atherosclerotic plaques, leading to myocardial infarctions, underpins most cardiovascular disease-related morbidity and mortality. However, the specific immune pathways that drive atherosclerotic plaque destabilization and rupture remain poorly understood. Moreover, there is critical debate in the field as to whether autoimmune responses might play a central role in atherosclerotic inflammation, disease progression and outcome. To explore this important avenue, we have used single-cell transcriptomics to dissect T cell immunity and clonality specifically in unstable versus stable atherosclerotic plaque in both humans and mice. We first identified that T cells are extensively activated and clonally expanded within plaque tissue. Moreover, we discovered differential T cell transcriptional landscapes in unstable versus stable plaque that support a direct and causal role for T cells in plaque destabilisation. Experimentally, we then demonstrate that CD8+ T cells are mechanistically critical to atherosclerosis and require their TCR to drive plaque expansion, vascular inflammation and plaque destabilisation. Combined, our data provide strong evidence that TCR-dependent CD8+ T cell responses are a critical player in atherosclerotic plaque destabilisation, support the concept of atherosclerotic autoimmunity, and identify multiple T cell phenotypes as potential therapeutic targets. Topic Categories Immune Mechanisms of Human Disease (HUM)

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Publication Details

Journal
The Journal of Immunology
Published
2025-11-01
DOI
https://doi.org/10.1093/jimmun/vkaf283.361
Primary Topic
Atherosclerosis and Cardiovascular Diseases
Type
article
Field-Weighted Citation Impact
0.00

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article

TCR-dependent CD8+ T cell responses drive atherosclerotic plaque instability 2443

Anna M.D. Watson, Alexander R. Pinto, Aidan P. G. Walsh, Thomas D. Otto et al.
The Journal of Immunology
Atherosclerosis and Cardiovascular Diseases
article

TCR-dependent CD8+ T cell responses drive atherosclerotic plaque instability 2443

Anna M.D. Watson, Alexander R. Pinto, Aidan P. G. Walsh, Thomas D. Otto, M. Lee, Axel Kallies, N. Dayawansa, Nicholas Borcherding, Nicholas A. Gherardin, Gabriella E. Farrugia, Karlheinz Peter, Marcel Michla, Megan K. L. MacLeod, Viktoria Bongcaron, Peter Kannelakis, Angela Huang, Jonathan Noonan, Alex Bobik, Thodur Vasudevan, Dale Ian Godfrey, Andrew James Murphy, Lisa M. Domke, Adam P. Uldrich, J Michael Kilby, Anastasia Barbaro-Wahl, Shania A Prijaya, Prerna Sharma, Xiaowei Wang, Ian Hsu, Yilu Huang
article en

Abstract

Abstract Description Atherosclerosis is a chronic inflammatory condition of the arterial vasculature. The rupture of atherosclerotic plaques, leading to myocardial infarctions, underpins most cardiovascular disease-related morbidity and mortality. However, the specific immune pathways that drive atherosclerotic plaque destabilization and rupture remain poorly understood. Moreover, there is critical debate in the field as to whether autoimmune responses might play a central role in atherosclerotic inflammation, disease progression and outcome. To explore this important avenue, we have used single-cell transcriptomics to dissect T cell immunity and clonality specifically in unstable versus stable atherosclerotic plaque in both humans and mice. We first identified that T cells are extensively activated and clonally expanded within plaque tissue. Moreover, we discovered differential T cell transcriptional landscapes in unstable versus stable plaque that support a direct and causal role for T cells in plaque destabilisation. Experimentally, we then demonstrate that CD8+ T cells are mechanistically critical to atherosclerosis and require their TCR to drive plaque expansion, vascular inflammation and plaque destabilisation. Combined, our data provide strong evidence that TCR-dependent CD8+ T cell responses are a critical player in atherosclerotic plaque destabilisation, support the concept of atherosclerotic autoimmunity, and identify multiple T cell phenotypes as potential therapeutic targets. Topic Categories Immune Mechanisms of Human Disease (HUM)

The Journal of ImmunologyVol. 214(Supplement_1)
Baker Heart and Diabetes Institute (AU), The University of Melbourne (AU), Washington University in St. Louis (US), The Alfred Hospital (AU), University of Glasgow (GB)
National Research Foundation, Sungkyunkwan University, National Research Foundation of Korea
Openalex Percentile: Top 61%
Atherosclerosis and Cardiovascular Diseases
DOIOpen Access PDFOpenAlex
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