TLR2-activated human langerhans cells promote Th17 polarization via IL-1beta, TGF-beta and IL-23
The cytokines IL-6, IL-1b, TGF-b, 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 cb was detected. To clarify if IL-171cells could arise per se by stimulated LC we did not repress Th1/Th2 driving pathways by antibodies inhibiting differentiation. In CD1c1/langerin1 monocyte-derived LC-like cells (MoLC), macrophage-activating lipopeptide 2, and peptidoglycan (PGN) induced the release of the cytokines IL-6, IL-1b, and IL-23. TGF-b, a cytokine required for LC differentiation and survival, was found to be secreted constitutively. Anti-TLR2 inhibited secretion of IL-6, IL-1b, and IL-23 by MoLC, while TGF-b was unaffected. The amount of IL-17 and the ratio of IL-17 to IFN-c expression was higher in MoLC- than in monocyte-derived DC-cocultured Th cells. Anti-IL-1b, -TGF-b 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.