title: Vessel wall-embedded dendritic cells induce T-cell autoreactivity and initiate vascular inflammation.
abstract: Human medium-sized and large arteries are targeted by inflammation with innate and adaptive immune responses occurring within the unique microspace of the vessel wall. How 3D spatial arrangements influence immune recognition and cellular response thresholds and which cell populations sense immunoactivating ligands and function as antigen-presenting cells are incompletely understood. To mimic the 3D context of human arteries, bioartificial arteries were engineered from collagen type I matrix, human vascular smooth muscle cells (VSMCs), and human endothelial cells and populated with cells implicated in antigen presentation and T-cell stimulation, including monocytes, macrophages, and myeloid dendritic cells (DCs). Responsiveness of wall-embedded antigen-presenting cells was probed with the Toll-like receptor ligand lipopolysaccharide, and inflammation was initiated by adding autologous CD4(+) T cells. DCs colonized the outermost VSMC layer, recapitulating their positioning at the media-adventitia border of normal arteries. Wall-embedded DCs responded to the microbial product lipopolysaccharide by entering the maturation program and upregulating the costimulatory ligand CD86. Activated DCs effectively stimulated autologous CD4 T cells, which produced the proinflammatory cytokine interferon-gamma and infiltrated deeply into the VSMC layer, causing matrix damage. Lipopolysaccharide-triggered macrophages were significantly less efficacious in recruiting T cells and promoting T-cell stimulation. CD14(+) monocytes, even when preactivated, failed to support initial steps of vascular wall inflammation. Innate immune cells, including monocytes, macrophages, and DCs, display differential functions in the vessel wall. DCs are superior in sensing pathogen-derived motifs and are highly efficient in breaking T-cell tolerance, guiding T cells toward proinflammatory and tissue-invasive behavior.
authors.affiliation: Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Ji W
authors.initials: JW
authors.lastname: Han
authors.forename: Kazunori
authors.initials: K
authors.lastname: Shimada
authors.forename: Wei
authors.initials: W
authors.lastname: Ma-Krupa
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Johnson
authors.forename: Robert M
authors.initials: RM
authors.lastname: Nerem
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D001158:Arteries / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D001167:Arteritis / Q000276:immunology*; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000276:immunology*; D051381:Rats; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D023822:Tissue Engineering; D051197:Toll-Like Receptor 4 / Q000187:drug effects
chemical_list: D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4