Getting to the Heart of the Matter: The Role of Regulatory T-Cells (Tregs) in Cardiovascular Disease (CVD) and Atherosclerosis

Abstract

Cardiovascular diseases (CVD) are the leading cause of mortality worldwide. Atherosclerosis is directly associated with CVD and is characterized by slow progressing inflammation which results in the deposition and accumulation of lipids beneath the endothelial layer in conductance and resistance arteries. Both chronic inflammation and disease progression have been associated with several risk factors, including but not limited to smoking, obesity, diabetes, genetic predisposition, hyperlipidemia, and hypertension. Currently, despite increasing incidence and significant expense on the healthcare system in both western and developing countries, there is no curative therapy for atherosclerosis. Instead patients rely on surgical intervention to avoid or revert vessel occlusion, and pharmacological management of the aforementioned risk factors. However, neither of these approaches completely resolve the underlying inflammatory environment which perpetuates the disease, nor do they result in plaque regression. As such, immunomodulation could provide a novel therapeutic option for atherosclerosis; shifting the balance from proatherogenic to athero-protective. Indeed, regulatory T-cells (Tregs), which constitute 5-10% of all CD4⁺ T lymphocytes in the peripheral blood, have been shown to be athero-protective and could function as new targets in both CVD and atherosclerosis. This review aims to give a comprehensive overview about the roles of Tregs in CVD, focusing on atherosclerosis.

Keywords: atherosclerosis; cardiovascular disease (CVD); hyperlipidemia; hypertension; regulatory T cells (Tregs).

Figure 1

Atherosclerotic disease progression. ROS produced by ECs, SMCs, neutrophils, and macrophages oxidized LDL in the sub-endothelial space. Emigrated monocytes become macrophages which uptake oxLDL, subsequently forming foam cells, that are unable to migrate to arterial lumen, accumulate in the sub-endothelial space and die forming a large plaque with a necrotic core. Rupture of this plaque leads to thrombus formation.

Figure 2

Suppressive mechanisms of Tregs in atherosclerosis. Tregs can directly produce suppressive cytokines and degradative enzymes such as perforin and granzyme that leads to apoptosis. Furthermore, Tregs have been observed to have direct effects on APC's via interaction with via CTLA-4, PD-L1/2, and LAG-3. They can also skew monocyte class switching, encouraging anti-inflammatory M2 macrophages formation which produced collagen and stabilizes the plaque. They can also decrease foam cell formation via the down-regulation of CD36 and CD204.