Association between CD8+ T-cell subsets and cardiovascular disease.

BACKGROUND: The findings of experimental studies suggest that the immune system plays a key role in atherosclerosis, but the clinical importance of different immune cells in cardiovascular disease remains poorly characterized. In this study we investigated the association between CD8(+) T cells and carotid disease as well as development of cardiovascular disease events. METHODS: The study cohort comprised 700 subjects from the cardiovascular arm of the Malmö Diet and Cancer Study. Peripheral blood mononuclear cells, obtained at the 1991-1994 baseline investigation and stored at -140 °C, were thawed and the different CD8(+) T-cell populations analysed by flow cytometry. Baseline carotid intima-media thickness and stenosis were assessed by ultrasonography and clinical events were monitored through validated national registers. RESULTS: Subjects with a high fraction of CD8(+) T cells were characterized by decreased cytokine release from activated leucocytes, metabolic signs of insulin resistance and increased incidence of coronary events; hazard ratios (95% confidence intervals) for the second and third tertiles of CD8(+) T cells were 2.57 (1.16, 5.67) and 2.61 (1.19, 5,71), respectively, in a Cox proportional hazards regression model. Correlations were found between the fraction of CD8(+) CD25(+) T cells and the degree of carotid stenosis (r = 0.11, P < 0.01), and between the CD8(+) CD56(-) IFN-γ(+) T-cell fraction and the degree of stenosis (r = -0.18, P < 0.005). The association between CD8(+) CD56(-) IFN-γ(+) T cells and carotid stenosis remained significant after controlling for major cardiovascular disease risk factors. CONCLUSION: This study provides prospective clinical evidence for a role of CD8(+) T cells in cardiovascular disease and suggests the existence of CD8(+) T-cell subsets with different pathological functions.

Evidence for a role of regulatory T cells in mediating the atheroprotective effect of apolipoprotein B peptide vaccine.

OBJECTIVES: Autoimmune responses against oxidized low-density lipoprotein are considered to play an important pro-inflammatory role in atherosclerosis and to promote disease progression. T-regulatory cells (Tregs) are immunosuppressive cells that have an important part in maintaining self-tolerance and protection against autoimmunity. We investigated whether aBp210, a prototype atherosclerosis vaccine based on a peptide sequence derived from apolipoprotein B, inhibits atherosclerosis through the activation of Tregs. DESIGN: Six-week-old Apoe(-/-) mice were immunized with aBp210 and received booster immunizations 3 and 5 weeks later, as well as 1 week before being killed at 25 weeks of age. RESULTS: At 12 weeks, immunized mice had increased expression of the Treg marker CD25 on circulating CD4 cells, and concanavalin A (Con A)-induced interferon-γ, interleukin (IL)-4, and IL-10 release from splenocytes was markedly depressed. At 25 weeks, there was a fivefold expansion of splenic CD4+ CD25+ Foxp3 Tregs, a 65% decrease in Con A-induced splenic T-cell proliferation and a 37% reduction in the development of atherosclerosis in immunized mice. Administration of blocking antibodies against CD25 neutralized aBp210-induced Treg activation as well as the reduction of atherosclerosis. CONCLUSIONS: The present findings demonstrate that immunization of Apoe(-/-) mice with the apolipoprotein B peptide vaccine aBp210 is associated with activation of Tregs. Administration of antibodies against CD25 results in depletion of Tregs and blocking of the atheroprotective effect of the vaccine. Modulation in atherosclerosis-related autoimmunity by antigen-specific activation of Tregs represents a novel approach for treatment of atherosclerosis.