Regulatory T cells as a new therapeutic target for atherosclerosis

Abstract

Atherosclerosis is an autoimmune disease caused by self- and non-self-antigens contributing to excessive activation of T and B cell immune responses. These responses further aggravate vascular infiammation and promote progression of atherosclerosis and vulnerability to plaques via releasing pro-infiammatory cytokines. Regulatory T cells (Tregs) as the major immunoregulatory cells, in particular, induce and maintain immune homeostasis and tolerance by suppressing the immune responses of various cells such as T and B cells, natural killer (NK) cells, monocytes, and dendritic cells (DCs), as well as by secreting inhibitory cytokines interleukin (IL)-10, IL-35 and transcription growth factor β (TGF-β) in both physiological and pathological states. Numerous evidence demonstrates that reduced numbers and dysfunction of Treg may be involveved in atherosclerosis pathogenesis. Increasing or restoring the numbers and improving the immunosuppressive capacity of Tregs may serve as a fundamental immunotherapy to treat atherosclerotic cardiovascular diseases. In this article, we briefiy present current knowledge of Treg subsets, summarize the relationship between Tregs and atherosclerosis development, and discuss the possibilities of regulating Tregs for prevention of atherosclerosis pathogenesis and enhancement of plaque stability. Although the exact molecular mechanisms of Treg-mediated protection against atherosclerosis remain to be elucidated, the strategies for targeting the regulation of Tregs may provide specific and significant approaches for the prevention and treatment of atherosclerotic cardiovascular diseases.

Keywords: atherosclerosis; cardiovascular diseases; immune regulation; regulatory T cells; treatment strategy.

Figure 1

The mechanism of Tregs in the protection against atherosclerosis. Through secretion of IL-10, IL-35, and TGF-β, Tregs decrease inflammatory cell recruitment and activation, inhibit effector T cells differentiation and inflammation, and promote SMC survival and proliferation and collagen biosynthesis. Accordingly, IL-10 induces the M1 macrophage switch to the M2 phenotype, which attenuates atherosclerosis by decreasing IFN-γ, IL-1β, and proteolytic enzyme production and promoting collagen synthesis and SMC proliferation. Moreover, Tregs inhibit T cell differentiation into Th1, Th2, and Th17 subtypes and suppress the immune and inflammatory responses by inhibiting pro-inflammatory cytokine IFN-γ production. Tregs also suppress B cell maturation, antibody production and immunoglobulin class switching and modulate B cell survival by secreting granzymes and perforin. Among other pathways, Tregs inhibit the function and maturation of DCs, induce immune tolerance of APCs, and suppress naive T cell activation by CTLA-4-, TGF-β- and IL-10-mediated mechanisms. Tregs enhance plaque stability by inhibiting monocyte recruitment and promoting SMC proliferation. Furthermore, Tregs inhibit lipid and foam cell formation by decreasing the expression of CD36 and SR-A and reduce plasma VLDL, LDL, and cholesterol levels.