Regulatory T cells prevent plaque disruption in apolipoprotein E-knockout mice

Abstract

CD4(+)CD25(+) regulatory T cells (Tregs) have received considerable interest in atherogenesis. We hypothesized that Tregs treatment may dose-dependently stabilize atherosclerotic plaques by inhibiting inflammatory cytokine secretion and matrix metalloproteinases (MMPs) expression and enhancing P4Hα1 expression in atherosclerotic lesions. We established a vulnerable carotid plaque model in apolipoprotein E- knockout mice (ApoE-/-). Mice were divided into control, phosphate buffered saline (PBS), small-dose Tregs, moderate-dose Tregs, large-dose Tregs and PC groups. Histopathological analysis showed that the plaque disruption rate was 50%, 50%, 43.8%, 12.5%, 12.5% and 43.8% in the control, PBS, small-dose Tregs, moderate-dose Tregs, large-dose Tregs and PC groups. Tregs treatment resulted in a significant decrease in the relative contents of macrophages and lipids and a substantial increase in those of SMCs and collagen in the carotid plaque, leading to an almost 50% reduction of plaque vulnerability index. Furthermore, Tregs treatment decreased the expression of proinflammatory cytokines, MMP-2 and MMP-9 but increased the expression of P4Hα1 both in vivo and in vitro. Most of these therapeutic effects of Tregs were found to be mediated by transforming growth factor and interleukin-10. Adoptive transfer of Tregs dose-dependently changed plaque composition to a stable plaque phenotype and lowered the incidence of plaque disruption in ApoE-/- mice. The major mechanisms involved reduced expression of inflammatory cytokines and MMP-2 and MMP-9, and enhanced expression of P4Hα1 in the carotid plaque. Tregs may provide a novel approach to the treatment of vulnerable plaques.