title: Toll-like receptor 4 engagement drives differentiation of human and murine dendritic cells from a pro- into an anti-inflammatory mode.
abstract: The dendritic cell (DC) coordinates innate and adaptive immunity to fight infections and cancer. Our observations reveal that DCs exposed to the microbial danger signal lipopolysaccharide (LPS) in the presence of interferon-γ (IFN-γ) acquire a continuously changing activation/maturation phenotype. The DCs' initial mode of action is pro-inflammatory via up-regulation among others of the signaling molecule interleukin (IL) 12, which polarizes IFN-γ secreting type 1 helper T-cells (Th1). Within 24 hours the same DC switches from the pro- into an anti-inflammatory phenotype. This is mediated by autocrine IL-10 release and secretion of soluble IL-2 receptor alpha (sIL-2RA) molecules. T-cells, when contacted with DCs during their anti-inflammatory phase loose their proliferative capacity and develop regulatory T-cell (Treg) -like anti-inflammatory functions indicated by IL-10 secretion and elevated FoxP3 levels. Studying the kinetics of IL-12 and IL-10 expression from LPS/IFN-γ activated myeloid DCs on a single cell level confirmed these observations. When T-cells are separated from DCs within 24 hours, they are spared from the anti-inflammatory DC activity. We conclude that, in addition to differentiation of DCs into distinct subsets, the observed sequential functional phases of DC differentiation permit the fine-tuning of an immune response. A better understanding of time-kinetic DC features is required for optimally exploiting the therapeutic capacity of DCs in cancer immune therapy.
authors: St. Anna Children's Cancer Research Institute, Laboratory of Tumor Immunology, Department of Pediatrics, Medical University Vienna, Austria.
authors: Romana
authors: R
authors: Luger
authors: Sneha
authors: S
authors: Valookaran
authors: Natalie
authors: N
authors: Knapp
authors: Caterina
authors: C
authors: Vizzardelli
authors: Alexander M
authors: AM
authors: Dohnal
authors: Thomas
authors: T
authors: Felzmann
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D051379:Mice; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D016207:Cytokines; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4