title: Human Langerhans cells selectively activated via Toll-like receptor 2 agonists acquire migratory and CD4+T cell stimulatory capacity.
abstract: In epidermal Langerhans cells (LCs), the expression pattern and the functions of TLRs have been poorly characterized. By using mAb, we show that LCs from human skin express TLR1, -2, -5, -6, and -9, the cognate receptors for detection of specific bacteria-derived molecules. As compared with other TLR agonists, LCs acquired a more matured phenotype when activated by specific bacterial or synthetic TLR2 agonists. In addition, monocyte-derived Langerin(+)/CD1c(+)LCs (CD1c(+)MoLCs) secreted higher amounts of IL-6 and TNF-alpha by stimulation via TLR2 than by stimulation via TLR3, -4, -5, -8, and -9. In contrast to MoLCs, dendritic cells, generated from the same donor monocytes, were activated by agonists of TLRs other than TLR2 as well. Lipopeptides triggering TLR2 induced IL-1R-associated kinase-1 phosphorylation and migration toward the chemokines CCL19 and CCL21 in epidermal LCs and CD1c(+)MoLCs. Up-regulation of CD86, CD83, and CCR7, TNF-alpha and IL-6, and NF-kappaB activation and proliferation of CD4(+)T cells could be inhibited TLR2-specific blockage using antibodies prior to TLR2 activation. Application of anti-TLR1, anti-TLR6, and anti-TLR2 indicated an exclusive role of TLR2 in IL-6 induction in human LCs. Collectively, our results show that TLR2 expressed by LCs mediates inflammatory responses to lipopeptides, which implicates a central role in sensing pathogens in human skin.
authors.affiliation: Institute of Molecular Biology and Bioinformatics, Charité CBF, Berlin, Germany. matthias.peiser@charite.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Peiser
authors.forename: Juliana
authors.initials: J
authors.lastname: Koeck
authors.forename: Carsten J
authors.initials: CJ
authors.lastname: Kirschning
authors.forename: Burghardt
authors.initials: B
authors.lastname: Wittig
authors.forename: Reinhard
authors.initials: R
authors.lastname: Wanner
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000502:physiology; D002465:Cell Movement; D000078404:Epidermal Cells; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D015850:Interleukin-6 / Q000378:metabolism; D007801:Langerhans Cells / Q000166:cytology / Q000276:immunology* / Q000502:physiology; D008074:Lipoproteins / Q000494:pharmacology; D008213:Lymphocyte Activation; D016328:NF-kappa B / Q000032:analysis; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D008074:Lipoproteins; D016328:NF-kappa B; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha