Published online before print February 5, 2008

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0807567

Received for publication August 24, 2007.
Revised December 5, 2007.
Accepted for publication December 12, 2007.

Article

Human Langerhans cells selectively activated via Toll-like receptor 2 agonists acquire migratory and CD4⁺T cell stimulatory capacity

Matthias Peiser ^*@, Juliana Koeck , Carsten J. Kirschning , Burghardt Wittig ^*, and Reinhard Wanner ^*

*Institute of Molecular Biology and Bioinformatics, Charité CBF, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, Berlin, Germany; and Institute of Microbiology, Technische Universität, München, Germany

^@ To whom correspondence should be addressed. E-mail: matthias.peiser{at}charite.de.

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- 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- and IL-6, and NF-B 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.

Key Words: TLR2 • dendritic cell • skin • peptidoglycan • lipopeptide • chemotaxis

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