PD-1 and Tim-3 Pathways Regulate CD8+ T Cells Function in Atherosclerosis

T cell-mediated immunity plays a significant role in the development of atherosclerosis (AS). There is increasing evidence that CD8(+) T cells are also involved in AS but their exact roles remain unclear. The inhibitory receptors programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain 3 (Tim-3) are well known inhibitory molecules that play a crucial role in regulating CD8(+) T cell activation or tolerance. Here, we demonstrate that the co-expression of PD-1 and Tim-3 on CD8(+) T cells is up-regulated in AS patients. PD-1(+) Tim-3(+) CD8(+) T cells are enriched for within the central T (T-CM) cell subset, with high proliferative activity and CD127 expression. Co-expression of PD-1 and Tim-3 on CD8(+) T cells is associated with increased anti-atherogenic cytokine production as well as decreased proatherogenic cytokine production. Blockade of PD-1 and Tim-3 results in a decrease of anti-atherogenic cytokine production by PD-1(+) Tim-3(+) CD8(+) T cells and in an augmentation of TNF-alpha and IFN-gamma production. These findings highlight the important role of the PD-1 and Tim-3 pathways in regulating CD8(+) T cells function in human AS.