Single-cell T cell receptor sequencing of paired human atherosclerotic plaques and blood reveals autoimmune-like features of expanded effector T cells

Abstract

Atherosclerosis is a lipid-driven chronic inflammatory disease; however, whether it can be classified as an autoimmune disease remains unclear. In this study, we applied single-cell T cell receptor seqencing (scTCR-seq) on human carotid artery plaques and matched peripheral blood mononuclear cell samples to assess the extent of TCR clonality and antigen-specific activation within the various T cell subsets. We observed the highest degree of plaque-specific clonal expansion in effector CD4+ T cells, and these clonally expanded T cells expressed genes such as CD69, FOS and FOSB, indicative of recent TCR engagement, suggesting antigen-specific stimulation. CellChat analysis suggested multiple potential interactions of these effector CD4+ T cells with foam cells. Finally, we integrated a published scTCR-seq dataset of the autoimmune disease psoriatic arthritis, and we report various commonalities between the two diseases. In conclusion, our data suggest that atherosclerosis has an autoimmune compondent driven by autoreactive CD4+ T cells.

Mouse Model of Heart Attack and Stroke Shows Improved Survival with MPO Inhibition

“…In addition to an increase in cluster 7, we found an increased proportion of cells in clusters 15 and 17 (T-cells) in WD+AZM198-fed SR-BI ∆CT/∆CT /Ldlr -/mice compared to mice fed WD (Extended Figure 7c,d). Interestingly, cluster 15 contains CD8 + Tcells that express both naïve T-cell markers such as Tcf7 and Lef1 as well as proliferation markers such Mki67 which have been previously documented in human atherosclerotic lesions 64 . The cells in cluster 17 appear to be CD4 + CD8 + double positive immature T-cells that express genes such as Tcf7, Lef1, Rag1, Ccr9 (Extended Data Figure 7e).…”

Resident Memory T Cells in the Atherosclerotic Lesion Associate With Reduced Macrophage Content and Increased Lesion Stability

“…Lesional T cells have been reported to express an activated phenotype and display signs of clonal expansion and tissue enrichment, implying recent activation through TCR-specific interactions. 6,28 Hence, it seems that merely a fraction of CD69-expressing cells in the lesion possess a T RM phenotype, while for the remaining cells potentially upregulated CD69 as a response to antigen recognition.…”

“…Human endarterectomy samples were digested into a single-cell suspension following a previously described protocol. 6 In brief, lesions were digested into a single-cell suspension by cutting the tissue into pieces of ≈1 mm 2 , followed by digestion with 2.5 mg/mL collagenase IV (Thermo Fisher Scientific), 0.25 mg/mL DNAse I (Sigma), 2.5 mg/mL Human Albumin Fraction V (MP Biomedicals) in RPMI 1640 for 30 minutes at 37 °C. After digestion, plaque tissue was mashed over a 70-µm strainer to create a single-cell suspension and washed in RPMI 1640.…”

Cardiovascular Brain Circuits

“…134,135 In murine atherosclerosis models and human diseased tissues, recent evidence is pointing to a bona fide autoimmune component for B cells 136 and more recently autoimmune T cells. 133,137,138 This data has important implications for understanding the poorly understood relation between bona fide autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis and atherosclerosis known to exacerbate each other. [139][140][141][142] There is recent progress in the area of the role and a detailed description of the contribution of different immune cell subsets to atherosclerotic lesion progression which can be found elsewhere.…”