TLR2-activated human langerhans cells promote Th17 polarization via IL-1beta, TGF-beta and IL-23

Eur J Immunol. 2009 May;39(5):1221-30. doi: 10.1002/eji.200838742.


The cytokines IL-6, IL-1beta, TGF-beta, and IL-23 are considered to promote Th17 commitment. Langerhans cells (LC) represent DC in the outer skin layers of the epidermis, an environment extensively exposed to pathogenic attack. The question whether organ-resident DC like LC can evoke Th17 immune response is still open. Our results show that upon stimulation by bacterial agonists, epidermal LC and LC-like cells TLR2-dependently acquire the capacity to polarize Th17 cells. In Th17 cells, expression of retinoid orphan receptor gammabeta was detected. To clarify if IL-17(+)cells could arise per se by stimulated LC we did not repress Th1/Th2 driving pathways by antibodies inhibiting differentiation. In CD1c(+)/langerin(+) monocyte-derived LC-like cells (MoLC), macrophage-activating lipopeptide 2, and peptidoglycan (PGN) induced the release of the cytokines IL-6, IL-1beta, and IL-23. TGF-beta, a cytokine required for LC differentiation and survival, was found to be secreted constitutively. Anti-TLR2 inhibited secretion of IL-6, IL-1beta, and IL-23 by MoLC, while TGF-beta was unaffected. The amount of IL-17 and the ratio of IL-17 to IFN-gamma expression was higher in MoLC- than in monocyte-derived DC-cocultured Th cells. Anti-IL-1beta, -TGF-beta and -IL-23 decreased the induction of Th17 cells. Interestingly, blockage of TLR2 on PGN-stimulated MoLC prevented polarization of Th cells into Th17 cells. Thus, our findings indicate a role of TLR2 in eliciting Th17 immune responses in inflamed skin.

MeSH terms

  • CD4-Positive T-Lymphocytes / immunology
  • Coculture Techniques
  • DNA, Bacterial / immunology
  • Female
  • Flow Cytometry
  • Humans
  • Interleukin-17 / immunology*
  • Interleukin-1beta / immunology*
  • Interleukin-23 Subunit p19 / immunology
  • Langerhans Cells / immunology*
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Poly I-C / immunology
  • Poly U / immunology
  • RNA / chemistry
  • RNA / genetics
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / immunology
  • Receptors, Thyroid Hormone / genetics
  • Receptors, Thyroid Hormone / immunology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Skin / cytology
  • Toll-Like Receptor 2 / antagonists & inhibitors
  • Toll-Like Receptor 2 / immunology*
  • Transforming Growth Factor beta / immunology*


  • DNA, Bacterial
  • Interleukin-17
  • Interleukin-1beta
  • Interleukin-23 Subunit p19
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RORC protein, human
  • Receptors, Retinoic Acid
  • Receptors, Thyroid Hormone
  • TLR2 protein, human
  • Toll-Like Receptor 2
  • Transforming Growth Factor beta
  • Poly U
  • RNA
  • Poly I-C