title: TLR-mediated induction of negative regulatory ligands on dendritic cells.
abstract: Dendritic cells (DCs) shape T-cell response patterns and determine early, intermediate, and late outcomes of immune recognition events. They either facilitate immunostimulation or induce tolerance, possibly determined by initial DC activation signals, such as binding Toll-like receptor (TLR) ligands. Here, we report that DC stimulation through the TLR3 ligand dsRNA [poly(I:C)] limits CD4 T-cell proliferation, curtailing adaptive immune responses. CD4+ T cells instructed by either lipopolysaccharide (LPS) or poly(I:C)-conditioned DCs promptly upregulated the activation marker CD69. Whereas LPS-pretreated DCs subsequently sustained T-cell clonal expansion, proliferation of CD4+ T cells exposed to poly(I:C)-pretreated DCs was markedly suppressed. This proliferative defect required DC-T cell contact, was independent of IFN-alpha, and was overcome by exogenous IL-2, indicating T-cell anergy. Coinciding with the downregulation, CD4+ T cells expressed the inhibitory receptor PD-1. Antibodies blocking the PD-1 ligand PD-L1 restored proliferation. dsRNA-stimulated DCs preferentially induced PD-L1, whereas poly(I:C) and LPS both upregulated the costimulatory molecule CD86 to a comparable extent. Poly(dA-dT), a ligand targeting the cytoplasmic RNA helicase pattern-recognition pathway, failed to selectively induce PD-L1 upregulation, assigning this effect to the TLR3 pathway. Poly(I:C)-conditioned DCs promoted accumulation of phosphorylated SHP-2, the intracellular phosphatase mediating PD-1 inhibitory effects. The ability of dsRNA to bias DC differentiation toward providing inhibitory signals to interacting CD4+ T cells may be instrumental in viral immune evasion. Conversely, TLR3 ligands may have therapeutic value in silencing pathogenic immune responses.
authors.affiliation: Kathleen B. and Mason I. Lowance Center for Human Immunology, Department of Medicine, Emory University School of Medicine, Room 1003 Woodruff Memorial Research Building, 101 Woodruff Circle, Atlanta, GA 30322, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gröschel
authors.forename: Kisha D
authors.initials: KD
authors.lastname: Piggott
authors.forename: Augusto
authors.initials: A
authors.lastname: Vaglio
authors.forename: Wei
authors.initials: W
authors.lastname: Ma-Krupa
authors.forename: Karnail
authors.initials: K
authors.lastname: Singh
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology; D008024:Ligands; D008070:Lipopolysaccharides / Q000276:immunology; D012330:RNA, Double-Stranded / Q000235:genetics / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000276:immunology*
chemical_list: D016898:Interferon-alpha; D008024:Ligands; D008070:Lipopolysaccharides; D012330:RNA, Double-Stranded; D051196:Toll-Like Receptor 3