Abstract 13409: Generation of CD8+ Effector Memory T cells by Diet-induced Hypercholesterolemia in apoE-/- Mice
Background: We recently reported that the cholesterol milieu affects T cell phenotype. Increasing evidence indicates a role for CD8+ T cells in atherosclerosis, yet the effect of hypercholesterolemia on CD8+ T cell effector phenotype and function remain unclear. To better understand the mechanistic role of CD8+ T cells in atherosclerosis, we investigated CD8+ T cell effector response and function in response to diet-induced hypercholesterolemia in apoE-/- mice.
Methods and Results: Seven week-old apoE-/- mice were fed either normal chow (NC, N=5) or western-type diet (WD, N=5) for 6 weeks and were euthanized at 13 weeks of age. Spleens were collected at euthanasia and stained for flow cytometry or subjected to CD8+ T cell isolation for use in cytolytic assays using oxLDL-primed macrophages as target cells. Serum cholesterol levels were significantly increased in WD compared to NC fed mice (1544±195 vs. 490±107 mg/dL, respectively; P<0.001). CD44(+)CD62L(-) Effector Memory (EM) CD8+ T cells were significantly increased in WD compared to NC fed mice (6.3±1.9% vs. 3.0±0.8%, respectively; P<0.01). There was no significant difference in CD44(-)CD62L(+) naïve CD8+ T cells (75.5±1.5% vs. 77.3±2.8%, respectively), and a slight reduction in CD44(+)CD62L(+) Central Memory (CM) CD8+ cells in WD compared to NC fed mice (9.0±0.9% vs. 11.1±1.6%, respectively; P<0.05). There were no observed differences in the CD8+ T cell TCR Vβ profile between the two groups. Cytolytic activity against oxLDL-primed macrophages was significantly increased in CD8+ T cells from WD compared to NC fed mice (9.7±4.8% vs. 4.0±1.7%, respectively; P<0.05; N=4 each). There was a highly significant positive correlation between serum cholesterol levels and CD44(+)CD62L(-) EM CD8+ T cells (R2=0.662, P=0.004).
Conclusion: Hypercholesterolemia induced by WD in apoE-/- mice results in increased CD8+ EM T cells with increased cytolytic activity. CD8+ EM T cells were significantly correlated with serum cholesterol levels. Our results highlight a novel relationship between hypercholesterolemia and T cell phenotype/function underscoring the need to develop new paradigms in the immune-inflammatory pathogenesis of atherosclerosis.
Author Disclosures: P.C. Dimayuga: None. K. Chyu: None. X. Zhao: None. J. Yano: None. J. Zhou: None. W. Lio: None. B. Cercek: None. P.K. Shah: None.
- © 2014 by American Heart Association, Inc.