Virus-associated CD8+ T-cells are not activated through antigen-mediated interaction inside atherosclerotic lesions

Jong, M.J.M. de; Schaftenaar, F.H.; Depuydt, M.A.C.; Vigario, F.L.; Janssen, G.M.C.; Peeters, J.A.H.M.; Goncalves, L.; Wezel, A.; Smeets, H.J.; Kuiper, J.; Bot, I.; Veelen, P. van; Sluetter, B.

doi:doi:10.1161/ATVBAHA.123.320539

INTRODUCTION:Viral infections have been associated with the progression of atherosclerosis and CD8⁺ T-cells directed against common viruses, such as influenza, Epstein-Barr virus, and cytomegalovirus, have been detected inside human atherosclerotic lesions. These virus-specific CD8⁺ T-cells have been hypothesized to contribute to the development of atherosclerosis; however, whether they affect disease progression directly remains unclear. In this study, we aimed to characterize the activation status of virus-specific CD8⁺ T-cells in the atherosclerotic lesion.METHODS:The presence, clonality, tissue enrichment, and phenotype of virus-associated CD8⁺ T-cells in atherosclerotic lesions were assessed by exploiting bulk T-cell receptor-β sequencing and single-cell T-cell receptor (α and β) sequencing datasets on human endarterectomy samples and patient-matched blood samples. To investigate if virus-specific CD8...Show moreINTRODUCTION:Viral infections have been associated with the progression of atherosclerosis and CD8⁺ T-cells directed against common viruses, such as influenza, Epstein-Barr virus, and cytomegalovirus, have been detected inside human atherosclerotic lesions. These virus-specific CD8⁺ T-cells have been hypothesized to contribute to the development of atherosclerosis; however, whether they affect disease progression directly remains unclear. In this study, we aimed to characterize the activation status of virus-specific CD8⁺ T-cells in the atherosclerotic lesion.METHODS:The presence, clonality, tissue enrichment, and phenotype of virus-associated CD8⁺ T-cells in atherosclerotic lesions were assessed by exploiting bulk T-cell receptor-β sequencing and single-cell T-cell receptor (α and β) sequencing datasets on human endarterectomy samples and patient-matched blood samples. To investigate if virus-specific CD8⁺ T-cells can be activated through T-cell receptor stimulation in the atherosclerotic lesion, the immunopeptidome of human plaques was determined.RESULTS:Virus-associated CD8⁺ T-cells accumulated more in the atherosclerotic lesion (mean=2.0%), compared with patient-matched blood samples (mean=1.4%; P=0.05), and were more clonally expanded and tissue enriched in the atherosclerotic lesion in comparison with nonassociated CD8⁺ T-cells from the lesion. Single-cell T-cell receptor sequencing and flow cytometry revealed that these virus-associated CD8⁺ T-cells were phenotypically highly similar to other CD8⁺ T-cells in the lesion and that both exhibited a more activated phenotype compared with circulating T-cells. Interestingly, virus-associated CD8⁺ T-cells are unlikely to be activated through antigen-specific interactions in the atherosclerotic lesion, as no virus-derived peptides were detected on HLA-I in the lesion.CONCLUSIONS:This study suggests that virus-specific CD8⁺ T-cells are tissue enriched in atherosclerotic lesions; however, their potential contribution to inflammation may involve antigen-independent mechanisms.Show less

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Virus-associated CD8+ T-cells are not activated through antigen-mediated interaction inside atherosclerotic lesions