CD8(+) T-Cell Deletion Suppressed the Development of Injury-Induced Experimental Neointimal Hyperplasia in Mice With or Without Chronic Stress.

Chronic stress exacerbates cardiovascular injury and remodeling. Given the pivotal roles that cytotoxic CD8(+) T cells play in pathobiology, we investigated potential role(s) of CD8(+) T cells in stress-related vascular remodeling in a mouse carotid injury model. Eight-week-old male wild-type (CD8a(+/+)) and CD8a knockout (CD8a(-/-)) mice underwent carotid artery ligation plus cuff placement (L + C) with or without being subjected to chronic stress. At surgery conducted 2 weeks later, L + C alone had significantly promoted carotid neointimal hyperplasia and induced an extensive infiltration of CD8(+) T cells into injured vascular tissues. Chronic stress further exacerbated neointimal formation and CD8(+) T-cell infiltration. Genetically deleting CD8(+) T cells significantly attenuated neointimal hyperplasia, collagen deposition, and proliferative PCNA-positive cells and reduced CD68-positive macrophage infiltration, the expressions of inflammatory genes (AT1R, galectin-3, MCP-1, VCAM-1, ICAM-1) and extracellular matrix-remodeling enzyme genes (MMP-2, MMP-9, cathepsin S, cathepsin K), and proliferative signaling-pathway proteins (p-Akt, p-p38, p-mTOR). Data from interferon (IFN)-γ knockout (IFN-γ(-/-)) mice administered an IFN-γ-neutralizing antibody or an adoptive transfer of CD8(+) T cells from IFN-γ(+/+) mice or IFN-γ(-/-) mice further confirmed the CD8(+) T-cell deletion-mediated protective effects against experimental neointimal hyperplasia in response to stress and injury. In vitro vascular smooth muscle cell experiments revealed that the cell migration and invasion abilities and mTOR/Akt signaling were sensitive to 5% stress serum from CD8a(+/+) mice. CD8(+) T-cell deletion thus appears to ameliorate vascular remodeling, suggesting that genetic CD8(+) T-cell modification might be a promising therapeutic target for managing proliferative vascular diseases in animals under chronic stress conditions.