Divergent T cell programs in plaque rupture and erosion revealed by single-cell multiomics in the OPTICO-ACS study
Hauke Horstmann, Christopher Wolfram, Lauren De Vore, Youssef S Abdelwahed, Anaïs Amend, Denitsa Meteva, Merlin Heiser, Philip Stapmanns, Claudio Seppelt, Lukas Zanders, Gregor Nelles, David Peters, Chantal Wientjens, Florian Zimmermann, Deniz Yücel, Marek Franitza, Kerstin Becker, Corinna Losert, Matthias Heinig, Konstantin Stark, Michael Joner, Alexander Lang, Thomas Riffelmacher, Norbert Gerdes, Stephan Baldus, Chiara Giannarelli, Dennis Wolf, Ulf Landmesser, Nicolle Kränkel, David M Leistner, Holger Winkels, Teresa GerhardtAbstract
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.