Background and aims: CD8+ T-cells have been attributed both atherogenic and atheroprotective properties, but analysis of CD8+ T-cells has mostly been restricted to the circulation and secondary lymphoid organs. The atherosclerotic lesion, however, is a complex microenvironment containing a plethora of inflammatory signals, which may affect CD8+ T-cell activation. Here, we address how this environment affects the functionality of CD8+ T-cells.
Methods and results: We compared the cytokine production of CD8+ T-cells derived from spleens and enzymatically digested aortas of apoE-/- mice with advanced atherosclerosis by flow cytometry. Aortic CD8+ T-cells produced decreased amounts of IFN-γ and TNF-α compared to their systemic counterparts. The observed dysfunctional phenotype of the lesion-derived CD8+ T-cells was not associated with classical exhaustion markers, but with increased expression of the ectonucleotidase CD39. Indeed, pharmacological inhibition of CD39 in apoE-/- mice partly restored cytokine production by CD8+ T-cells. Using a bone-marrow transplantation approach, we show that TCR signaling is required to induce CD39 expression on CD8+ T-cells in atherosclerotic lesions. Importantly, analysis of human endarterectomy samples showed a strong microenvironment specific upregulation of CD39 on CD8+ T-cells in the plaques of human patients compared to matched blood samples.
Conclusions: Our results suggest that the continuous TCR signaling in the atherosclerotic environment in the vessel wall induces an immune regulatory CD8+ T-cell phenotype that is associated with decreased cytokine production through increased CD39 expression in both a murine atherosclerotic model and in atherosclerosis patients. This provides a new understanding of immune regulation by CD8+ T-cells in atherosclerosis.
Keywords: Atherosclerosis; CD39; CD8(+) T-cells; Exhaustion.
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.