The Pro-inflammatory Functions of Type 1 CD 8+ T Cells and Interleukin-17-producing Cluster of Differentiation 8+ T Cells are Exhausted by Cholesterol in Atherosclerosis.

Abstract

Background: CD8+ T cells have been found to accumulate in atherosclerotic plaques. However, the specific role of CD8+ T cell subsets in the development of atherosclerosis is still not fully understood.

Objective: To investigate the presence and functions of type 1 CD8+ T (Tc1) cells and interleukin-17 (IL-17)-producing CD8+ T (Tc17) cells.

Methods: Apolipoprotein E-deficient mice were fed a high-fat diet to induce atherosclerosis. Flow cytometry was used to identify and isolate aortic CD8+ T cell subsets, which were then cultured in vitro to assess their pro-inflammatory activities. The cholesterol content of the CD8+ T cell subsets was quantified.

Results: T-box expressed in T cells (T-bet)+ Tc1 cells and retinoic acid-related orphan receptor gamma t (RORγt)+ Tc17 cells were found in the atherosclerotic aorta. Aortic CD8+ T cells showed lower pro-inflammatory activity compared to splenic counterparts, with less interferon-gamma (IFN-γ) (P <0.01) and tumor necrosis factor-alpha (TNF-α) production (P <0.01). Surprisingly, aortic CD8+ T cells expressed little IL-17 and interleukin-21 (IL-21) despite the presence of Tc17 cells. Aortic Tc1 and Tc17 cells expressed high levels of 2B4 and programmed cell death protein 1 (PD-1). Furthermore, aortic Tc1 and Tc17 cells had higher cholesterol contents than splenic CD8+ T cells (P <0.05, respectively). Cholesterol treatment decreased IFN-γ expression in Tc1 cells (P <0.001) and reduced IL-17 expression in Tc17 cells (P <0.001). Additionally, cholesterol up-regulated 2B4 and PD-1 on Tc1 (P <0.001) and Tc17 cells (P <0.001).

Conclusion: Aortic CD8+ T cells, particularly aortic Tc17 cells, are functionally exhausted in atherosclerosis, possibly due to the influence of cholesterol.