Atherosclerotic lesions are populated by cells of the innate and adaptive immune system, including CD8+ T cells. The CD8+ T cell infiltrate has recently been characterized in mouse and human atherosclerosis and revealed activated, cytotoxic, and possibly dysfunctional and exhausted cell phenotypes. In mouse models of atherosclerosis, antibody-mediated depletion of CD8+ T cells ameliorates atherosclerosis. CD8+ T cells control monopoiesis and macrophage accumulation in early atherosclerosis. In addition, CD8+ T cells exert cytotoxic functions in atherosclerotic plaques and contribute to macrophage cell death and necrotic core formation. CD8+ T cell activation may be antigen-specific, and epitopes of atherosclerosis-relevant antigens may be targets of CD8+ T cells and their cytotoxic activity. CD8+ T cell functions are tightly controlled by costimulatory and coinhibitory immune checkpoints. Subsets of regulatory CD25+CD8+ T cells with immunosuppressive functions can inhibit atherosclerosis. Importantly, local cytotoxic CD8+ T cell responses may trigger endothelial damage and plaque erosion in acute coronary syndromes. Understanding the complex role of CD8+ T cells in atherosclerosis may pave the way for defining novel treatment approaches in atherosclerosis. In this review article, we discuss these aspects, highlighting the emerging and critical role of CD8+ T cells in atherosclerosis.

Aims Atherosclerosis is a chronic inflammatory disease of the vessel wall controlled by local and systemic immune responses. The role of interleukin-23 receptor (IL-23R), expressed in adaptive immune cells (mainly T helper 17 cells) and γδ T cells, in atherosclerosis is only incompletely understood. Here we investigated the vascular cell types expressing IL-23R and addressed the function of IL-23R and γδ T cells in atherosclerosis. Method and results IL-23R+ cells were frequently found in the aortic root in contrast to the aorta in low density lipoprotein receptor deficient IL-23R reporter mice (Ldlr-/-Il23rgfp/+), and mostly identified as γδ T cells that express IL-17 and GM-CSF. scRNA-seq confirmed γδ T cells as the main cell type expressing Il23r and Il17a in the aorta. Ldlr-/-Il23rgfp/gfp mice deficient in IL-23R showed a loss of IL-23R+ cells in the vasculature, and had reduced atherosclerotic lesion formation in the aortic root compared to Ldlr-/- controls after 6 weeks of high fat diet feeding. In contrast, Ldlr-/-Tcrδ-/- mice lacking all γδ T cells displayed unaltered early atherosclerotic lesion formation compared to Ldlr-/- mice. In both HFD-fed Ldlr-/-Il23rgfp/gfp and Ldlr-/-Tcrδ-/- mice a reduction in the plaque necrotic core area was noted as well as an expansion of splenic regulatory T cells. In vitro, exposure of bone marrow-derived macrophages to both IL-17A and GM-CSF induced cell necrosis, and necroptotic RIP3K and MLKL expression, as well as inflammatory mediators. Conclusions IL-23R+ γδ T cells are predominantly found in the aortic root rather than the aorta and promote early atherosclerotic lesion formation, plaque necrosis and inflammation at this site. Targeting IL-23R may thus be explored as a therapeutic approach to mitigate atherosclerotic lesion development. Translational Perspective The mechanisms and cell types contributing to early inflammation and lesion formation are incompletely understood. Here we demonstrate that the aortic root harbors a population of IL23R-dependent γδ T cells that can release IL-17 and GM-CSF, and both cytokines together induce macrophage inflammation and necroptosis. IL-23R+ γδ T cells locally promote early lesion formation in the aortic root and contribute to the expansion of the necrotic core, a hallmark of vulnerable atherosclerotic lesions. Targeting IL-23R or IL-23 itself could thus be further explored as a therapeutic option in early atherosclerosis.

The significantly larger WO volume fraction for the malignant tumors was probably related to the increased vascularity associated with tumor angiogenesis. The results suggest that the WO volume fraction biomarker has potential to improve the computer-based assessment of breast MRI by greatly increasing the PPV of breast biopsies and potentially significantly reducing the number of unnecessary biopsies without compromising sensitivity.

The purpose of this study was to evaluate using lesion washout (WO) volume fraction as a biomarker to improve the characterization of suspicious breast lesions. Study lesions consisted of a total of 60 malignant tumors (BI‐RADS 6) and 62 suspicious lesions (BI‐RADS 4 or 5). The biopsies of these suspicious lesions resulted in a total of 30 malignant tumors and 32 benign lesions, respectively, yielding a 48.4% positive predictive value (PPV) of the biopsies. The mean and standard deviation of the lesion WO volume fraction of these 60 BI‐RADS 6 malignant tumors were first computed to establish a 99% sensitivity threshold value for malignant tumors, and then the biomarker was used to characterize the suspicious lesions. Using the biomarker would characterize all the malignant tumors as malignant, 12 out of the 32 benign lesions as benign, potentially resulting in a 24% improvement rate in the PPV of the biopsies (from 48.4% to 60%) and consequently a 22.5% reduction rate in the false‐positive rate of benign biopsies (from 51.6% to 40%). The lesion WO volume fraction biomarker could improve the computer‐based assessment of breast MRI by increasing the PPV of breast biopsies and reducing the number of unnecessary biopsies without compromising sensitivity.PACS number: 87.61.Tg, 87.19.Xj

No abstract