Atherosclerosis

2019

DOI: 10.1016/j.atherosclerosis.2019.04.217

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CD39 identifies a microenvironment-specific anti-inflammatory CD8+ T-cell population in atherosclerotic lesions

Janine van Duijn

¹

,

Marit van Elsas

²

,

³

et al.

Abstract: • CD8 + T-cells in atherosclerotic lesions show impaired IFN-γ and TNF-α production, associated with expression of CD39. • TCR signaling is required for the upregulation of CD39 + on lesional CD8 + T-cells. • Pharmacological inhibition of CD39 partly restores cytokine production of CD8 + T-cells in the atherosclerotic lesions. • CD8 + T-cells from human lesions display increased expression of CD39 compared to their circulating counterparts.

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Modulation Of T Lymphocytes By Purinergic Signaling During A1

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Cited by 16 publications

(17 citation statements)

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“…This could indicate that not the cytotoxic but the more quiescent CD8 + T-cell subsets are responding to plaque-specific antigens and may be more relevant in the pathogenesis of atherosclerosis. Using experimental mouse models of atherosclerosis it has been shown that the majority of CD8 + T cells in the plaque are antigen-specific, 38 but so far little is known regarding the plaque-antigen(s) they respond to. Whereas CD4 + T cells have been shown to respond to (ox)LDL ([oxidized] low-density lipoprotein) and its related apo B 100 peptide, plaque-antigen(s) for CD8 + remain mostly indefinable.…”

Section: Resultsmentioning

confidence: 99%

Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics

¹

,

²

,

³

et al. 2020

Circulation Research

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Rationale: Atherosclerotic lesions are known for their cellular heterogeneity, yet the molecular complexity within the cells of human plaques have not been fully assessed. Objective: Using single-cell transcriptomics and chromatin accessibility we gained a better understanding of the pathophysiology underlying human atherosclerosis. Methods and Results: We performed single-cell RNA and single-cell ATAC sequencing on human carotid atherosclerotic plaques to define the cells at play and determine their transcriptomic and epigenomic characteristics. We identified 14 distinct cell populations including endothelial cells, smooth muscle cells, mast cells, B cells, myeloid cells, and T cells and identified multiple cellular activation states and suggested cellular interconversions. Within the endothelial cell population we defined subsets with angiogenic capacity plus clear signs of endothelial to mesenchymal transition. CD4 + and CD8 + T cells showed activation-based subclasses, each with a gradual decline from a cytotoxic to a more quiescent phenotype. Myeloid cells included two populations of pro-inflammatory macrophages showing IL1B or TNF expression as well as a foam cell-like population expressing TREM2 and displaying a fibrosis-promoting phenotype. ATACseq data identified specific transcription factors associated with the myeloid subpopulation and T cell cytokine profiles underlying mutual activation between both cell types. Finally, cardiovascular disease susceptibility genes identified using public GWAS data were particularly enriched in lesional macrophages, endothelial and smooth muscle cells. Conclusions: This study provides a transcriptome-based cellular landscape of human atherosclerotic plaques and highlights cellular plasticity and intercellular communication at the site of disease. This detailed definition of cell communities at play in atherosclerosis will facilitate cell-based mapping of novel interventional targets with direct functional relevance for the treatment of human disease.

“…This could indicate that not the cytotoxic but the more quiescent CD8 + T-cell subsets are responding to plaque-specific antigens and may be more relevant in the pathogenesis of atherosclerosis. Using experimental mouse models of atherosclerosis it has been shown that the majority of CD8 + T cells in the plaque are antigen-specific, 38 but so far little is known regarding the plaque-antigen(s) they respond to. Whereas CD4 + T cells have been shown to respond to (ox)LDL ([oxidized] low-density lipoprotein) and its related apo B 100 peptide, plaque-antigen(s) for CD8 + remain mostly indefinable.…”

Section: Resultsmentioning

confidence: 99%

Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics

¹

,

²

,

³

et al. 2020

Circulation Research

Self Cite

View full text Add to dashboard Cite

Rationale: Atherosclerotic lesions are known for their cellular heterogeneity, yet the molecular complexity within the cells of human plaques have not been fully assessed. Objective: Using single-cell transcriptomics and chromatin accessibility we gained a better understanding of the pathophysiology underlying human atherosclerosis. Methods and Results: We performed single-cell RNA and single-cell ATAC sequencing on human carotid atherosclerotic plaques to define the cells at play and determine their transcriptomic and epigenomic characteristics. We identified 14 distinct cell populations including endothelial cells, smooth muscle cells, mast cells, B cells, myeloid cells, and T cells and identified multiple cellular activation states and suggested cellular interconversions. Within the endothelial cell population we defined subsets with angiogenic capacity plus clear signs of endothelial to mesenchymal transition. CD4 + and CD8 + T cells showed activation-based subclasses, each with a gradual decline from a cytotoxic to a more quiescent phenotype. Myeloid cells included two populations of pro-inflammatory macrophages showing IL1B or TNF expression as well as a foam cell-like population expressing TREM2 and displaying a fibrosis-promoting phenotype. ATACseq data identified specific transcription factors associated with the myeloid subpopulation and T cell cytokine profiles underlying mutual activation between both cell types. Finally, cardiovascular disease susceptibility genes identified using public GWAS data were particularly enriched in lesional macrophages, endothelial and smooth muscle cells. Conclusions: This study provides a transcriptome-based cellular landscape of human atherosclerotic plaques and highlights cellular plasticity and intercellular communication at the site of disease. This detailed definition of cell communities at play in atherosclerosis will facilitate cell-based mapping of novel interventional targets with direct functional relevance for the treatment of human disease.

“…Naive CD8+ T cells can be differentiated into different subsets with diverse immune functions. 26 It has been previously reported that CD8+ regulatory T cells, which produce predominantly anti-inflammatory cytokines like IL-10, can be generated from circulating naive CD8+ T cells of healthy donors 27 or identified in the heart, spleen, and circulating blood of rats after myocardial infarction, 28,29 as well as in livers of patients with chronic hepatitis C virus infection. 30 In this study, the human CD248+CD8+ T cells also exhibited immune regulatory potential, because they express IL-10 but not IL-1β/INF-γ.…”

Section: Discussionmentioning

confidence: 99%

CD248+CD8+ T lymphocytes suppress pathological vascular remodeling in human thoracic aortic aneurysms

¹

,

Wu²,

³

et al. 2020

Exp Biol Med (Maywood)

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Aortic aneurysms are characterized by vascular inflammation, neovascularization, and extracellular matrix destruction of the aortic wall. Although experimental studies indicate a potential role of CD248 in microvessel remodeling, the functions of CD248 in human vascular pathologies remain unexplored. Here we aimed to study how CD248 interferes with pathological vascular remodeling of human aortic aneurysms. Immunofluorescent staining showed that CD248 expression was mainly localized in the CD8+ T cells infiltrating in the adventitia and media of aortic walls of patients with ascending thoracic aortic aneurysms. qPCR and immunofluorescent staining analyses revealed increased aortic CD248 expression and infiltrating CD248+CD8+ T cells in aortic aneurysms than in nonaneurysmal aortas. Flow cytometry analysis of human peripheral blood further identified a fraction of circulating CD248+ cells which was confined in the CD8+ T-cell compartment. The increased infiltrating of CD248+CD8+ T cells was coincident with reduced circulating CD248+CD8+ T cells in patients with ascending TAA when compared with patients with coronary artery diseases and healthy donors. The CD248+CD8+ T cells were characterized by upregulated IL-10 and downregulated IL-1β/INF-γ expression when compared with CD248-CD8+ T cells. Moreover, when co-cultured with human aortic endothelial cells, the CD248+CD8+ T cells not only downregulated endothelial expression of ICAM1/VCAM1 and MMP2/3 but also suppressed endothelial migration. This study shows that CD248 reduces pathological vascular remodeling via anti-inflammatory CD248+CD8+ T cells, revealing a CD248-mediated cellular mechanism against human aortic aneurysms. Impact statement In spite of recent evidence indicating that CD248 is linked to microvasculature remodeling, immune response, and MMP activity, the functions of CD248 in human TAA remain unexplored. In this work, by analyzing cellular components of in situ as well as of blood circulation of human TAA, we have identified a novel T cell subset, the CD248+CD8+ T cells, which exhibits anti-inflammatory properties, and that we have also provided the first evidence that these cells not only suppress endothelial expression of ICAM1/VCAM1 and MMP2/3, but also inhibit endothelial migration, thus uncovering a CD248-mediated cellular mechanism against pathological vascular remodeling in human aortic aneurysms.

“…However, a recent report has shed light on this issue and on the involvement of CD39 ectonucleotidase in conferring a regulatory and atheroprotective phenotype to CD8 + cells. This is associated with a reduction in cytokine production through increased CD39 expression in both mouse and human atherosclerotic lesions ( 132 ).…”

Section: Modulation Of T Lymphocytes By Purinergic Signaling During Amentioning

confidence: 99%

Purinergic Signaling in Controlling Macrophage and T Cell Functions During Atherosclerosis Development

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²

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³

et al. 2021

Front. Immunol.

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Atherosclerosis is a hardening and narrowing of arteries causing a reduction of blood flow. It is a leading cause of death in industrialized countries as it causes heart attacks, strokes, and peripheral vascular disease. Pathogenesis of the atherosclerotic lesion (atheroma) relies on the accumulation of cholesterol-containing low-density lipoproteins (LDL) and on changes of artery endothelium that becomes adhesive for monocytes and lymphocytes. Immunomediated inflammatory response stimulated by lipoprotein oxidation, cytokine secretion and release of pro-inflammatory mediators, worsens the pathological context by amplifying tissue damage to the arterial lining and increasing flow-limiting stenosis. Formation of thrombi upon rupture of the endothelium and the fibrous cup may also occur, triggering thrombosis often threatening the patient’s life. Purinergic signaling, i.e., cell responses induced by stimulation of P2 and P1 membrane receptors for the extracellular nucleotides (ATP, ADP, UTP, and UDP) and nucleosides (adenosine), has been implicated in modulating the immunological response in atherosclerotic cardiovascular disease. In this review we will describe advancements in the understanding of purinergic modulation of the two main immune cells involved in atherogenesis, i.e., monocytes/macrophages and T lymphocytes, highlighting modulation of pro- and anti-atherosclerotic mediated responses of purinergic signaling in these cells and providing new insights to point out their potential clinical significance.

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