Treating Atherosclerosis With Regulatory T Cells

Abstract

Regulatory T cells (Tregs) play an important role in the regulation of T cell-mediated immune responses through suppression of T cell proliferation and secretion of inhibitory cytokines such as IL-10 and TGF-β. Impaired Treg numbers and function have been associated with numerous diseases and an imbalance between pro-inflammatory/pro-atherogenic cells and Tregs promotes atherosclerotic disease. Restoration of this balance by inducing Tregs has great therapeutic potential to prevent cardiovascular disease. In addition to suppressing differentiation and function of effector T cells, Tregs have been shown to induce anti-inflammatory macrophages, inhibit foam cell formation and to influence cholesterol metabolism. Furthermore, Tregs suppress immune responses of endothelial cells and innate lymphoid cells. In this review we focus on the recent knowledge on Treg subsets, their activity and function in atherosclerosis and discuss promising strategies to use Tregs as a therapeutic tool to prevent cardiovascular disease.

MicroRNA-33–dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis

“…41). Impaired Treg numbers and function are found in patients with cardiovascular disease compared with healthy controls, and studies in mice indicate that Treg numbers in plaques decline with time of Western diet feeding, resulting in an accumulation of effector T cells that promote atherosclerosis (41). We observed a similar decline in plaque macrophage expression of Aldh1a2 with atherosclerosis progression, suggesting that the loss of this iTreg differentiation signal may contribute to the decline.…”

“…41). To determine whether inhibition of miR-33 in macrophages could promote Treg differentiation, we cocultured naive T cells with macrophages that were transfected with anti-miR-33 or control oligonucleotides ( Figure 6A).…”

“…Tregs exert immunosuppressive functions through their expression of IL-10 and TGF-β and have been shown to protect from atherosclerosis by suppressing effector Th1 and Th17 T cells, dendritic cell activation and migration, endothelial cell activation, and macrophage foam cell formation (reviewed in ref. 41). Impaired Treg numbers and function are found in patients with cardiovascular disease compared with healthy controls, and studies in mice indicate that Treg numbers in plaques decline with time of Western diet feeding, resulting in an accumulation of effector T cells that promote atherosclerosis (41).…”

Low TLR7 gene expression in atherosclerotic plaques is associated with major adverse cardio- and cerebrovascular events

“…Recent studies have identified subtypes of T cells and macrophages that do not necessarily drive pathogenesis but may mediate healing, likely by primarily eliciting anti-inflammatory responses. 18,19 Regarding the downstream effects of TLR7 activation, two recent studies have implicated TLR7 in the control or abatement of inflammation and in the adaptive immune response in both macrophages 16 and T cells, 17 cell types which are frequently found in atherosclerotic lesions. In an experimental study of airway inflammation, imiquimod promoted the resolution of inflammation by inducing the lipid mediator resolvin D in murine macrophages, 16 an effect that has also been observed in vitro in human monocytes.…”

Beyond vascular inflammation—recent advances in understanding atherosclerosis

“…Although some high affinity self-recognizing T cells are removed in the thymus by negative selection, it is important to recognize that essentially all T cells in an organism not exposed to pathogens are (positively) selected for self-antigens 132, 133 . The effect of Tregs has been extensively tested in the setting of atherosclerotic disease 134 . From a functional point of view, nT regs are considered anti-inflammatory immune cells, classically defined by co-expression of IL-2 receptor, CD25, the forkhead transcription factor (FoxP)-3, and the co-stimulatory molecule CTLA-4 135 .…”