Toll-like receptor 4 engagement drives differentiation of human and murine dendritic cells from a pro- into an anti-inflammatory mode

PLoS One. 2013;8(2):e54879. doi: 10.1371/journal.pone.0054879. Epub 2013 Feb 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology*
  • Cytokines / metabolism
  • Dendritic Cells / cytology*
  • Dendritic Cells / metabolism
  • Humans
  • Inflammation / physiopathology*
  • Mice
  • Toll-Like Receptor 4 / physiology*

Substances

  • Cytokines
  • TLR4 protein, human
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4

Grants and funding

The authors are grateful to the The St. Anna Children’s Cancer Research Institute (CCRI) and its many private donors for financing this research project. The work was also supported by grants from the City of Vienna (Vienna Business Agency, WWFF/ZIT), the Austrian government (Austrian Research Promotion Fund, FFG and FWF), and the EU (EU Framework Program 7) awarded to the CCRI and to Activartis Biotech GmbH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.