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.

Induction of antigen-specific cytotoxic T lymphocytes by fusion cells generated from allogeneic plasmacytoid dendritic and tumor cells

“…The binding of the pathogen-associated microbial pattern molecule LPS to Toll-like receptor (TLR) 4 on human MoDCs signals danger, which induces a potent immune stimulatory phenotype that is characterized by the release of IL-12p70 (18,19). Our finding that a pDC line activated with LPS is more active compared to unstimulated pDCs suggests that this TLR4 agonist plays a role in the activation of pDC functions (11).…”

Dendritic Cells and Their Multiple Roles during Malaria Infection

“…Different classes of PRRs were discovered in the last decades and include membrane anchored receptors such as toll-like receptors (TLRs) [ 9 ] and C-type lectin receptors (CLRs) [ 10 ], besides the cytoplasmic nucleotide-binding oligomerization domain- (Nod-) like receptors (NLRs), RIG-I-like receptors (RLRs), and AIM-2-like receptors [ 11 , 12 ], as well as a family of enzymes that function as intracellular sensors of nucleic acids, including OAS proteins and cGAS [ 12 ]. These PRRs are capable of triggering complex intracellular signals that stimulate DC maturation, increase the expression of major histocompatibility complex (MHC) and costimulatory molecules, and promote proinflammatory cytokines expression [ 13 , 14 ]. Thus, in a context of infection and inflammation, DCs can identify the presence of pathogens through PRRs and induce adaptive immune responses [ 13 ].…”

Pathogen-Associated Molecular Patterns Induced Crosstalk between Dendritic Cells, T Helper Cells, and Natural Killer Helper Cells Can Improve Dendritic Cell Vaccination

“…Most of the cytokines produced by moDC are released within the first 24 h [ 63 ]. In addition, we and others previously showed that in 6 h-matured DC the cytokine induction program is irreversibly primed [ 7 , 64 , 65 ]. Clinical trials employ diverse strategies to mature the DC.…”