TLR2-activated human langerhans cells promote Th17 polarization via IL-1beta, TGF-beta and IL-23.
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.
Charité - University Medicine Berlin, Institute of Molecular Biology and Bioinformatics, Berlin, Germany.
Ehsan
E
Aliahmadi
Robert
R
Gramlich
Andreas
A
Grützkau
Manuel
M
Hitzler
Melanie
M
Krüger
Ria
R
Baumgrass
Maximilian
M
Schreiner
Burghardt
B
Wittig
Reinhard
R
Wanner
Matthias
M
Peiser
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018920:Coculture Techniques; D004269:DNA, Bacterial / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology*; D053760:Interleukin-23 Subunit p19 / Q000276:immunology; D007801:Langerhans Cells / Q000276:immunology*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011070:Poly I-C / Q000276:immunology; D011072:Poly U / Q000276:immunology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000276:immunology; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000166:cytology; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*
D004269:DNA, Bacterial; D020381:Interleukin-17; D053583:Interleukin-1beta; D053760:Interleukin-23 Subunit p19; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D016212:Transforming Growth Factor beta; D011072:Poly U; D012313:RNA; D011070:Poly I-C