Pathogen-Sensing Plasmacytoid Dendritic Cells Stimulate Cytotoxic T-Cell Function in the Atherosclerotic Plaque Through Interferon-

Background—Unstable atherosclerotic plaque is characterized by an infiltrate of inflammatory cells. Both macrophages and T cells have been implicated in mediating the tissue injury leading to plaque rupture; however, signals regulating their activation remain unidentified. Infectious episodes have been suspected to render plaques vulnerable to rupture. We therefore explored whether plasmacytoid dendritic cells (pDCs) that specialize in sensing bacterial and viral products can regulate effector functions of plaque-residing T cells and thus connect host infection and plaque instability. Methods and Results—pDCs were identified in 53% of carotid atheromas (n 30) in which they localized to the shoulder region and produced the potent immunoregulatory cytokine interferon (INF). IFNtranscript concentrations in atheroma tissues correlated strongly with plaque instability (P 0.0001). Plaque-residing pDCs responded to pathogenderived motifs, CpG-containing oligodeoxynucleotides binding to toll-like receptor 9, with enhanced IFNtranscription (P 0.03) and secretion (P 0.007). IFNemerged as a potent regulator of T-cell function, even in the absence of antigen recognition. Specifically, IFNinduced a 10-fold increase of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) on the surface of CD4 T cells (P 0.0001) and enabled them to effectively kill vascular smooth muscle cells (P 0.0003). Conclusions—pDCs in atherosclerotic plaque sense microbial motifs and amplify cytolytic T-cell functions, thus providing a link between host-infectious episodes and acute immune-mediated complications of atherosclerosis. (Circulation. 2006;114:2482-2489.)