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(Circulation. 2006;114:2482-2489.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

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

Alexander Niessner, MD; Kayoko Sato, MD, PhD; Elliot L. Chaikof, MD, PhD; Ines Colmegna, MD; Jörg J. Goronzy, MD, PhD; Cornelia M. Weyand, MD, PhD

From the Kathleen B. and Mason I. Lowance Center for Human Immunology, Department of Medicine (A.N., K.S., I.C., J.J.G., C.M.W.), and Department of Surgery, Division of Vascular Surgery (E.L.C.), Emory University School of Medicine, Atlanta, Ga.

Correspondence to Cornelia M. Weyand, MD, PhD, Lowance Center for Human Immunology, Emory University School of Medicine, 101 Woodruff Circle, 1003 WMRB, Atlanta, GA 30322. E-mail cweyand{at}emory.edu

Received June 9, 2006; revision received September 13, 2006; accepted September 29, 2006.

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)-. IFN- transcript concentrations in atheroma tissues correlated strongly with plaque instability (P<0.0001). Plaque-residing pDCs responded to pathogen-derived motifs, CpG-containing oligodeoxynucleotides binding to toll-like receptor 9, with enhanced IFN- transcription (P=0.03) and secretion (P=0.007). IFN- emerged as a potent regulator of T-cell function, even in the absence of antigen recognition. Specifically, IFN- induced 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.

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