Regulatory T cells in cardiovascular diseases

Abstract

Inflammation is essential in the initial development and progression of many cardiovascular diseases involving innate and adaptive immune responses. The role of CD4(+)CD25(+)FOXP3(+) regulatory T (TREG) cells in the modulation of inflammation and immunity has received increasing attention. Given the important role of TREG cells in the induction and maintenance of immune homeostasis and tolerance, dysregulation in the generation or function of TREG cells can trigger abnormal immune responses and lead to pathology. A wealth of evidence from experimental and clinical studies has indicated that TREG cells might have an important role in protecting against cardiovascular disease, in particular atherosclerosis and abdominal aortic aneurysm. In this Review, we provide an overview of the roles of TREG cells in the pathogenesis of a number of cardiovascular diseases, including atherosclerosis, hypertension, ischaemic stroke, abdominal aortic aneurysm, Kawasaki disease, pulmonary arterial hypertension, myocardial infarction and remodelling, postischaemic neovascularization, myocarditis and dilated cardiomyopathy, and heart failure. Although the exact molecular mechanisms underlying the cardioprotective effects of TREG cells are still to be elucidated, targeted therapies with TREG cells might provide a promising and novel future approach to the prevention and treatment of cardiovascular diseases.

Figure 1 ∣. Differentiation of naive T cells into T cell subpopulations.

In response to stimulation with antigens or cytokines, naive T cells can differentiate into distinct subpopulations including T_H1, T_H2, T_H17, and T_REG cells. APC, antigen presenting cell; FOXP3, forkhead box P3; GATA3, trans-acting T-cell specific transcription factor; IFN, interferon; RORγt, RAR-related orphan receptor gamma; TGF, transforming growth factor; T^REG cell, regulatory T cell; TNF, tumour necrosis factor.

Figure 2 ∣. Mechanisms of T_REG cell-mediated suppression and the implicative pathways.

A variety of molecular mechanisms might operate in a complementary fashion to contribute to T_REG cell-mediated suppression. All these mechanisms can be classified into two major categories: cell-contact-independent mechanisms (production of inhibitory cytokines, deprivation of IL-2 and ATP/ADP) and cell-contact-dependent mechanisms (induction of cytolysis, modulation of APCs). CTLA-4, cytotoxicT lymphocyte-associated antigen-4; DC, dendritic cell; ITAM, immunoreceptor tyrosine-based activation motif; LAG3, lymphocyte activation gene 3; MHC, major histocompatibility complex; TGF, transforming growth factor; TREG cell, regulatory T cell.

Figure 3 ∣. Underlying mechanisms of T_REG cells in atherosclerosis.

T_REG cells improve endothelial function, inhibit B cells, inhibit activation and migration of DCs, increase SMC and collagen content, modulate lipid metabolism, and suppress macrophage and CD4+ T cell accumulation, foam cell formation, proinflammatory cytokines, and MMPs secretion. Inhibitory cytokines, including TGF-β, IL-10, and IL-35, are essential for T_REG cell-mediated suppression of atherosclerosis. CTLA-4, cytotoxic T lymphocyte-associated antigen-4; DC, dendritic cell; EC, endothelial cell; LAG3, lymphocyte activation gene 3; MHC, major histocompatibility complex; MMP, matrix metalloproteinase; PD-1, programmed cell death protein 1; PD-L1/2, programmed death ligand 1/2; SMC, smooth muscle cell; TGF, transforming growth factor; T_REG cell, regulatory T cell.

Figure 4 ∣. Underlying mechanisms of T_REG cells in AAA.

T_REG cells inhibit macrophage and CD4+ T cell accumulation, proinflammatory cytokines, and MMPs expression, preserve aortic medial SMC, suppress apoptosis and oxidative stress, and promote anti-inflammatory cytokine production in the abdominal aorta. AAA, abdominal aortic aneurysm; CTLA-4, cytotoxic T lymphocyte-associated antigen-4; MMP, matrix metalloproteinase; SMC, smooth muscle cell; TGF, transforming growth factor; T_REG cell, regulatory T cell.