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Pairing of single-cell RNA analysis and T cell antigen receptor profiling indicates breakdown of T cell tolerance checkpoints in atherosclerosis.
- Source :
-
Nature cardiovascular research [Nat Cardiovasc Res] 2023 Mar; Vol. 2 (3), pp. 290-306. Date of Electronic Publication: 2023 Feb 23. - Publication Year :
- 2023
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Abstract
- Atherosclerotic plaques form in the inner layer of arteries triggering heart attacks and strokes. Although T cells have been detected in atherosclerosis, tolerance dysfunction as a disease driver remains unexplored. Here we examine tolerance checkpoints in atherosclerotic plaques, artery tertiary lymphoid organs and lymph nodes in mice burdened by advanced atherosclerosis, via single-cell RNA sequencing paired with T cell antigen receptor sequencing. Complex patterns of deteriorating peripheral T cell tolerance were observed being most pronounced in plaques followed by artery tertiary lymphoid organs, lymph nodes and blood. Affected checkpoints included clonal expansion of CD4 <superscript>+</superscript> , CD8 <superscript>+</superscript> and regulatory T cells; aberrant tolerance-regulating transcripts of clonally expanded T cells; T cell exhaustion; T <subscript>reg</subscript> -TH <subscript>17</subscript> T cell conversion; and dysfunctional antigen presentation. Moreover, single-cell RNA-sequencing profiles of human plaques revealed that the CD8 <superscript>+</superscript> T cell tolerance dysfunction observed in mouse plaques was shared in human coronary and carotid artery plaques. Thus, our data support the concept of atherosclerosis as a bona fide T cell autoimmune disease targeting the arterial wall.<br />Competing Interests: Competing interests S.K.M., A.J.R.H. and C.Y. declare competing interests. C.Y., S.K.M. and A.J.R.H. are owners of Easemedcontrol R&D & Co KG, Munich, Germany; C.Z., A.J.R.H. and C.Y. are inventors on a pending patent application related to the diagnostics and therapeutic usages of TCRs/B cell receptors to treat atherosclerosis. The remaining authors declare no competing interests.
Details
- Language :
- English
- ISSN :
- 2731-0590
- Volume :
- 2
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Nature cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 37621765
- Full Text :
- https://doi.org/10.1038/s44161-023-00218-w