Pathogen-sensing plasmacytoid dendritic cells stimulate cytotoxic T-cell function in the atherosclerotic plaque through interferon-alpha.
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.


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)-alpha. IFN-alpha 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-alpha transcription (P=0.03) and secretion (P=0.007). IFN-alpha emerged as a potent regulator of T-cell function, even in the absence of antigen recognition. Specifically, IFN-alpha 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.
Niessner
Alexander
A
Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory University School of Medicine, 101 Woodruff Circle, Atlanta, GA 30322, USA.
Sato
Kayoko
K
Chaikof
Elliot L
EL
Colmegna
Ines
I
Goronzy
Jörg J
JJ
Weyand
Cornelia M
CM
D000368:Aged; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D050197:Atherosclerosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D017848:Blood-Borne Pathogens; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D016893:Carotid Stenosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism
D016898:Interferon-alpha; C495371:TLR9 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051217:Toll-Like Receptor 9