Abstract
T-cell activation is characteristic during the development of atherosclerosis. While overall T-cell responses have been implicated in disease acceleration, regulatory T cells (Tregs) exhibit atheroprotective effects. The expression of the enzyme indoleamine 2,3-dioxygenase-1 (IDO1), which catalyzes the degradation of tryptophan (Trp) along the kynurenine pathway, has been implicated in the induction and expansion of Treg populations. Hence, Tregs can reciprocally promote IDO1 expression in dendritic cells (DCs) via reverse signaling mechanisms during antigen presentation. In this study, we hypothesize that triggering the “Treg/IDO axis” in the artery wall is atheroprotective. We show that apolipoprotein B100-pulsed tumor growth factor beta 2-treated tolerogenic DCs promote de novo FoxP3+ Treg expansion in vivo. This local increase in Treg numbers is associated with increased vascular IDO1 expression and a robust reduction in the atherosclerotic burden. Using human primary cell cultures, we show for the first time that IDO1 expression and activity can be regulated by cytotoxic T-lymphocyte associated protein-4, which is a constitutive molecule expressed and secreted by Tregs, in smooth muscle cells, endothelial cells, and macrophages. Altogether, our data suggest that Tregs and IDO1-mediated Trp metabolism can mutually regulate one another in the vessel wall to promote vascular tolerance mechanisms that limit inflammation and atherosclerosis.
Highlights
Atherosclerosis is a chronic inflammatory disease initiated by the retention and accumulation of low-density lipoprotein (LDL) in the artery wall
We show that promoting the expansion of antigen-specific FoxP3+ Tregs in the artery wall with an injection of tumor growth factor beta 2 (TGFβ2)-treated and apolipoprotein B100 (ApoB100)-pulsed tolerogenic dendritic cells (DCs) leads to increased IDO1 expression and atheroprotection
The untreated DCs were characterized as CD11c+MHC-IIhighCD11b+DEC205+
Summary
Atherosclerosis is a chronic inflammatory disease initiated by the retention and accumulation of low-density lipoprotein (LDL) in the artery wall. Treg/IDO Axis Promotes Atheroprotective Mechanisms have been identified as critical for protection against disease [2]. Tregs can exert their antiatherogenic effects via the local secretion of anti-inflammatory cytokines, such as transforming growth factor beta (TGFβ) and interleukin 10 (IL-10), or by cell-to-cell contact [3]. Indoleamine 2,3-dioxygenase-1 (IDO1), which is the rate-limiting enzyme catalyzing the production of metabolites in the Kynurenine pathway of tryptophan (Trp) degradation, has been implicated in the regulation of T-cell effector responses and the expansion of Tregs [7,8,9]. The inhibition of Trp metabolism using the IDO inhibitor 1-methyl tryptophan (1-MT) or the genetic ablation of IDO1 in hypercholesterolemic mice results in a substantial increase in vascular inflammation and accelerated plaque formation [10, 11]
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