Divergent effects of mycobacterial cell wall glycolipids on maturation and function of human monocyte-derived dendritic cells

PLoS One. 2012;7(8):e42515. doi: 10.1371/journal.pone.0042515. Epub 2012 Aug 3.

Abstract

Background: Mycobacterium tuberculosis (Mtb) is able to evade the immune defenses and may persist for years, decades and even lifelong in the infected host. Mtb cell wall components may contribute to such persistence by modulating several pivotal types of immune cells. Dendritic cells (DCs) are the most potent antigen-presenting cells and hence play a crucial role in the initial immune response to infections by connecting the innate with the adaptive immune system.

Principal findings: We investigated the effects of two of the major mycobacterial cell wall-associated types of glycolipids, mannose-capped lipoarabinomannan (ManLAM) and phosphatidylinositol mannosides (PIMs) purified from the Mtb strains H37Rv and Mycobacterium bovis, on the maturation and cytokine profiles of immature human monocyte-derived DCs. ManLAM from Mtb H37Rv stimulated the release of pro-inflammatory cytokines TNF, IL-12, and IL-6 and expression of co-stimulatory (CD80, CD86) and antigen-presenting molecules (MHC class II). ManLAM from M. bovis also induced TNF, IL-12 and IL-6 but at significantly lower levels. Importantly, while ManLAM was found to augment LPS-induced DC maturation and pro-inflammatory cytokine production, addition of PIMs from both Mtb H37Rv and M. bovis strongly reduced this stimulatory effect.

Conclusions: These results indicate that the mycobacterial cell wall contains macromolecules of glycolipid nature which are able to induce strong and divergent effects on human DCs; i.e while ManLAM is immune-stimulatory, PIMs act as powerful inhibitors of DC cytokine responses. Thus PIMs may be important Mtb-associated virulence factors contributing to the pathogenesis of tuberculosis disease. These findings may also aid in the understanding of some earlier conflicting reports on the immunomodulatory effects exerted by different ManLAM preparations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers / metabolism
  • Cell Differentiation / drug effects*
  • Cell Wall / chemistry*
  • Cytokines / biosynthesis
  • Dendritic Cells / cytology*
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism*
  • Electrophoresis, Polyacrylamide Gel
  • Genes, Reporter
  • Glycolipids / pharmacology*
  • Humans
  • Inflammation Mediators / metabolism
  • Limulus Test
  • Lipopeptides / pharmacology
  • Lipopolysaccharides / chemistry
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / isolation & purification
  • Lipopolysaccharides / pharmacology
  • Monocytes / cytology*
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Mycobacterium / chemistry*
  • Mycobacterium bovis / metabolism
  • Mycobacterium tuberculosis / metabolism
  • Phosphatidylinositols / chemistry
  • Phosphatidylinositols / immunology
  • Phosphatidylinositols / isolation & purification
  • Phosphatidylinositols / pharmacology
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / metabolism

Substances

  • Biomarkers
  • Cytokines
  • Glycolipids
  • Inflammation Mediators
  • Lipopeptides
  • Lipopolysaccharides
  • Phosphatidylinositols
  • TLR2 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • lipoarabinomannan
  • phosphatidylinositol mannoside

Grant support

This work was supported by European Commission Grant MEST-CT-2005-020872 (to J.M. and A.P), and by Swedish Research Council Grants K2007-58X-13027 (to G.K.) and K2010-79X-21374-01-3 (to A.P.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.