Self-glycolipids modulate dendritic cells changing the cytokine profiles of committed autoreactive T cells

PLoS One. 2012;7(12):e52639. doi: 10.1371/journal.pone.0052639. Epub 2012 Dec 20.

Abstract

The impact of glycolipids of non-mammalian origin on autoimmune inflammation has become widely recognized. Here we report that the naturally occurring mammalian glycolipids, sulfatide and β-GalCer, affect the differentiation and the quality of antigen presentation by monocyte-derived dendritic cells (DCs). In response to sulfatide and β-GalCer, monocytes develop into immature DCs with higher expression of HLA-DR and CD86 but lower expression of CD80, CD40 and CD1a and lower production of IL-12 compared to non-modulated DCs. Self-glycolipid-modulated DCs responded to lipopolysaccharide (LPS) by changing phenotype but preserved low IL-12 production. Sulfatide, in particular, reduced the capacity of DCs to stimulate autoreactive Glutamic Acid Decarboxylase (GAD65) - specific T cell response and promoted IL-10 production by the GAD65-specific clone. Since sulfatide and β-GalCer induced toll-like receptor (TLR)-mediated signaling, we hypothesize that self-glycolipids deliver a (tolerogenic) polarizing signal to differentiating DCs, facilitating the maintenance of self-tolerance under proinflammatory conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoimmunity*
  • Cell Differentiation / drug effects*
  • Cell Line
  • Cells, Cultured
  • Cytokines / immunology
  • Cytokines / metabolism*
  • Dendritic Cells / cytology*
  • Dendritic Cells / drug effects*
  • Dendritic Cells / metabolism
  • Galactosylceramides / pharmacology
  • Glycolipids / pharmacology*
  • Humans
  • Phenotype
  • Signal Transduction / drug effects
  • Sulfoglycosphingolipids / pharmacology
  • T-Lymphocytes / immunology*
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / metabolism

Substances

  • Cytokines
  • Galactosylceramides
  • Glycolipids
  • Sulfoglycosphingolipids
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4

Grants and funding

This work has been supported by the Dutch Diabetes Research Foundation (Expert Center Grant 2008.40.001), the Juvenile Diabetes Research Foundation, the Netherlands Organization for Scientific Research (NWO-VICI, 918.86.611), the European Union (FP7-NAIMIT, number 241447), the Lundbeck Foundation, and the Danish Council for Independent Research | Medical Sciences (number 271-06-0424). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.