Divergent T cell programs in plaque rupture and erosion revealed by single-cell multiomics in the OPTICO-ACS study

AIMS: Plaque erosion accounts for up to 40% of acute coronary syndromes. Unlike plaque rupture, erosion is characterized by thrombus formation on an intact fibrous cap following endothelial denudation. Rupture is associated with broad inflammatory activation, whereas erosion features accumulation of specific immune cells, particularly CD4+ and CD8+ T cells. Their functional programming remains insufficiently defined.The objective was to characterize intracoronary and peripheral T cell phenotypes, activation programs, and clonal architecture in acute coronary syndromes caused by plaque erosion compared with plaque rupture. METHODS AND RESULTS: We prospectively enrolled 133 consecutive patients with acute coronary syndromes in whom plaque erosion or rupture was classified by optical coherence tomography. Blood was sampled from the coronary segment proximal to the lesion and from the peripheral circulation. T cell phenotypes were assessed by flow cytometry and plasma proteomics. In a subgroup, intracoronary samples underwent CITE-seq, integrating single-cell transcriptomics with surface protein profiling, together with paired T cell receptor sequencing. RESULTS: Flow cytometry demonstrated enrichment of activated memory helper and cytotoxic T cells with anti-inflammatory features at erosion sites, in contrast to predominantly naive and pro-inflammatory T cells in rupture. CITE-seq revealed erosion-specific activation of pathways related to proliferation, adhesion, and tissue repair, whereas T cells in rupture displayed enhanced inflammatory pathways. Functional validation confirmed greater IL-2/IFN-γ induction in rupture-associated memory T cells and greater IL-10 induction in erosion-associated Tregs. T cell receptor sequencing showed greater clonal expansion in erosion, suggesting antigen-experienced clonal selection, whereas rupture exhibited broader and less focused clonal diversity. CONCLUSIONS: Plaque erosion and plaque rupture show fundamentally different T cell immune profiles. Erosion is marked by memory-skewed, clonally expanded regulatory and cytotoxic T cell subsets, while rupture is characterized by proinflammatory phenotypes, diverse T cell receptor repertoires, and heightened inflammatory signaling. These findings support morphology-tailored immunotherapeutic approaches, including established anti-inflammatory strategies for rupture and selective T cell-directed interventions for erosion.

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Publication Details

Journal
Cardiovascular Research
Published
2026-10-30
DOI
https://doi.org/10.1093/cvr/cvag258
Primary Topic
Atherosclerosis and Cardiovascular Diseases
Type
article
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article

Divergent T cell programs in plaque rupture and erosion revealed by single-cell multiomics in the OPTICO-ACS study

Holger Winkels, Merlin Heiser, Norbert Gerdes, David M. Leistner et al.
Cardiovascular Research
Atherosclerosis and Cardiovascular Diseases
article

Divergent T cell programs in plaque rupture and erosion revealed by single-cell multiomics in the OPTICO-ACS study

Holger Winkels, Merlin Heiser, Norbert Gerdes, David M. Leistner, Matthias Heinig, Corinna Losert, Christopher Wolfram, Denitsa Meteva, Kerstin Becker, Dennis Wolf, Teresa Gerhardt, Konstantin Stark, Anaïs Amend, Stephan Ernst Baldus, Gregor Nelles, Claudio Seppelt, Lukas Zanders, Chiara Giannarelli, Youssef S. Abdelwahed, Hauke Horstmann, Chantal Wientjens, Lauren De Vore, Thomas Riffelmacher, Marek Franitza, Ulf Landmesser, Michael Joner, Philip Stapmanns, Nicolle Kränkel, Deniz Yucel, Florian Zimmermann, Alexander Lang, David Peters
article en

Abstract

AIMS: Plaque erosion accounts for up to 40% of acute coronary syndromes. Unlike plaque rupture, erosion is characterized by thrombus formation on an intact fibrous cap following endothelial denudation. Rupture is associated with broad inflammatory activation, whereas erosion features accumulation of specific immune cells, particularly CD4+ and CD8+ T cells. Their functional programming remains insufficiently defined.The objective was to characterize intracoronary and peripheral T cell phenotypes, activation programs, and clonal architecture in acute coronary syndromes caused by plaque erosion compared with plaque rupture. METHODS AND RESULTS: We prospectively enrolled 133 consecutive patients with acute coronary syndromes in whom plaque erosion or rupture was classified by optical coherence tomography. Blood was sampled from the coronary segment proximal to the lesion and from the peripheral circulation. T cell phenotypes were assessed by flow cytometry and plasma proteomics. In a subgroup, intracoronary samples underwent CITE-seq, integrating single-cell transcriptomics with surface protein profiling, together with paired T cell receptor sequencing. RESULTS: Flow cytometry demonstrated enrichment of activated memory helper and cytotoxic T cells with anti-inflammatory features at erosion sites, in contrast to predominantly naive and pro-inflammatory T cells in rupture. CITE-seq revealed erosion-specific activation of pathways related to proliferation, adhesion, and tissue repair, whereas T cells in rupture displayed enhanced inflammatory pathways. Functional validation confirmed greater IL-2/IFN-γ induction in rupture-associated memory T cells and greater IL-10 induction in erosion-associated Tregs. T cell receptor sequencing showed greater clonal expansion in erosion, suggesting antigen-experienced clonal selection, whereas rupture exhibited broader and less focused clonal diversity. CONCLUSIONS: Plaque erosion and plaque rupture show fundamentally different T cell immune profiles. Erosion is marked by memory-skewed, clonally expanded regulatory and cytotoxic T cell subsets, while rupture is characterized by proinflammatory phenotypes, diverse T cell receptor repertoires, and heightened inflammatory signaling. These findings support morphology-tailored immunotherapeutic approaches, including established anti-inflammatory strategies for rupture and selective T cell-directed interventions for erosion.

Cardiovascular Research
Goethe University Frankfurt (DE), Goethe-Institute United Kingdom (GB), University of Freiburg (DE), University of Cologne (DE), University Medical Center Freiburg (DE), Helmholtz Zentrum München (DE), LMU Klinikum (DE), Humboldt-Universität zu Berlin (DE), NYU Langone Health (US), Düsseldorf University Hospital (DE), Deutsches Herzzentrum der Charité (DE), German Centre for Cardiovascular Research (DE), University Hospital Frankfurt (DE), Deutsches Herzzentrum München (DE), Institute of Computational Biology (DE), Heinrich Heine University Düsseldorf (DE), New York University (US), Technical University of Munich (DE), Charité - Universitätsmedizin Berlin (DE), Ludwig-Maximilians-Universität München (DE)
Openalex Percentile: Top 18%
Atherosclerosis and Cardiovascular Diseases
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