Indoleamine 2,3-Dioxygenase-Expressing Aortic Plasmacytoid Dendritic Cells Protect against Atherosclerosis by Induction of Regulatory T Cells

Plasmacytoid dendritic cells (pDCs) are unique bone-marrow-derived cells that produce large amounts of type I interferon in response to microbial stimulation. Furthermore, pDCs also promote T cell tolerance in sterile-inflammation conditions. However, the immunomodulatory role of aortic pDCs in atherosclerosis has been poorly understood. Here, we identified functional mouse and human pDCs in the aortic intima and showed that selective, inducible pDC depletion in mice exacerbates atherosclerosis. Aortic pDCs expressed CCR9 and indoleamine 2,3-dioxygenase 1 (IDO-1), an enzyme involved in driving the generation of regulatory T cells (Tregs). As a consequence, loss of pDCs resulted in decreased numbers of Tregs and reduced IL-10 levels in the aorta. Moreover, antigen presentation by pDCs expanded antigen-specific Tregs in the atherosclerotic aorta. Notably, Tregs ablation affected pDC homeostasis in diseased aorta. Accordingly, pDCs in human atherosclerotic aortas colocalized with Tregs. Collectively, we identified a mechanism of atheroprotection mediated by tolerogenic aortic pDCs. [Display omitted] •Mouse and human aorta contain type I interferon-producing pDCs•Selective depletion of aortic pDCs with BDCA2-DTR mice aggravates atherosclerosis•pDCs and Tregs are concomitantly induced and colocalized in atherosclerotic intima•Local induction of Tregs by aortic IDO-1+ pDCs prevents atherosclerosis Dendritic cells (DCs) bridge innate and adaptive immunity. Yun et al. investigated the role of bone-marrow-derived plasmacytoid dendritic cells (pDCs), which produce type I interferon in response to viral infection, in atherosclerosis in mouse and humans. Local induction of Tregs by aortic IDO-1+ pDCs prevents atherosclerosis.