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

Abstract

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.

No Significant Association Between Plasma Endosialin Levels and the Presence or Severity of Coronary Artery Disease

“…Furthermore, endosialin-knockout mice were reported to be protected against arterial thrombosis [6]. An immunofluorescence analysis also showed increased endosialin expression and infiltrating CD8 T cells in aortic aneurysm specimens, suggesting a role of endosialin in vascular remodeling [3].…”

“…Since endosialin is suggested to play a role in the progression of atherosclerosis [3,4,6], we hypothesized that plasma endosialin levels in patients with CAD would be high. Our present study is the first to report plasma endosialin levels in patients with CAD.…”

“…Endosialin, also called tumor endothelial marker-1 (TEM-1) or CD248, is a 165-kDa transmembrane glycoprotein that is comprised of a N-terminal extracellular domain, a Sushi domain and three epidermal growth factor (EGF)-like domains and that was initially identified on the blood vessels of tumors and was recognized as an abnormally expressed marker of tumor vascular endothelial cells [1][2][3]. However, subsequent studies reported that endosialin is not expressed by endothelial cells but by perivascular cells, such as vascular smooth muscle cells, fibroblasts, and CD8 T cells [3][4][5]. Endosialin expression is also low in normal perivascular cells.…”

Polymorphisms of Pro-Inflammatory IL-6 and IL-1β Cytokines in Ascending Aortic Aneurysms as Genetic Modifiers and Predictive and Prognostic Biomarkers

“…However, the phenotypes of the T CD4+, CD8+, and B cell subpopulations were not analyzed in our study, as well as gene expression and cytokine production. In fact, it has recently been reported that the cytokines produced by CD4+ and CD8 + T-lymphocytes and their subsets, such as CD248+ CD8+ T cells [47], play a causative role in the initiation and progression, as well as in the suppression, of aorta remodeling associated with onset of pathological conditions, such as aorta dilatation and aneurysm development [46,48]. Of note, for example, is the role of the abovementioned CD248+ CD8 + T [47] cells subset and its cytokine profile, that has been recently demonstrated to suppress the pathological vascular remodeling in human TAAA.…”

“…In fact, it has recently been reported that the cytokines produced by CD4+ and CD8 + T-lymphocytes and their subsets, such as CD248+ CD8+ T cells [47], play a causative role in the initiation and progression, as well as in the suppression, of aorta remodeling associated with onset of pathological conditions, such as aorta dilatation and aneurysm development [46,48]. Of note, for example, is the role of the abovementioned CD248+ CD8 + T [47] cells subset and its cytokine profile, that has been recently demonstrated to suppress the pathological vascular remodeling in human TAAA. This underlines the imperative necessity to investigate the type of T subsets in the aneurysm aorta tissues and their cytokine profile.…”