Crosstalk between lipoproteins and leukocytes: role of T cell cholesterol efflux pathways in aging and atherosclerosis

Cardiovascular disease (CVD) is one of the leading causes of death worldwide and atherosclerosis is the primary underlying cause. Main risk factors for atherosclerosis are elevated plasma low-density lipoprotein-cholesterol (LDL-c) levels and inflammation. Leukocytosis, the expansion of white blood cells, positively associates with CVD in humans, independent of inflammation. Studies in animal models have demonstrated that high-density lipoprotein-cholesterol (HDL-c) suppresses leukocytosis. We found a negative association between HDL-c and blood leukocytes in the LifeLines DEEP cohort, as such providing translational evidence for the findings in animal models. Leukocytosis in humans with myeloproliferative diseases is accompanied by low plasma LDL-c levels. Regardless, these patients are at increased risk of CVD. We propose that this is due to leukocytosis, and that stem cells take up high amounts of LDL-c to induce their proliferation leading to leukocytosis, which decreases plasma LDL-c. We also focused on a specific leukocyte subset, T cells. During atherogenesis and aging, T cells accumulate cholesterol leading to differentiation into distinct subsets with either pro- or anti-inflammatory characteristics. To investigate the effect of T cell cholesterol accumulation on T cell aging and atherosclerosis, we generated a mouse model with combined deficiency of the cholesterol transporters ATP Binding Cassette A1 and G1 (ABCA1/ABCG1) specifically in T cells. T cell Abca1/Abcg1 deficiency increased T cell apoptosis and senescence, and decreased atherosclerosis in middle-aged mice. Our findings suggest that T cell cholesterol efflux pathways are crucial in maintaining peripheral T cell numbers and T cell tolerance, especially during aging.