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Human Langerhans Cells Express a Specific TLR Profile and Differentially Respond to Viruses and Gram-Positive Bacteria¹

Vincent Flacher^2,*, Marielle Bouschbacher, Estelle Verronèse, Catherine Massacrier^*, Vanja Sisirak, Odile Berthier-Vergnes, Blandine de Saint-Vis^*, Christophe Caux^*,, Colette Dezutter-Dambuyant, Serge Lebecque^3,* and Jenny Valladeau^4,

^* Laboratory for Immunological Research, Schering-Plough, Dardilly, France; Université Claude Bernard–Lyon I, Centre Hospitalier Edouard Herriot, Lyon, France; and Centre Léon Bérard, Lyon, France

Dendritic cells (DC) are APCs essential for the development of primary immune responses. In pluristratified epithelia, Langerhans cells (LC) are a critical subset of DC which take up Ags and migrate toward lymph nodes upon inflammatory stimuli. TLR allow detection of pathogen-associated molecular patterns (PAMP) by different DC subsets. The repertoire of TLR expressed by human LC is uncharacterized and their ability to directly respond to PAMP has not been systematically investigated. In this study, we show for the first time that freshly purified LC from human skin express mRNA encoding TLR1, TLR2, TLR3, TLR5, TLR6 and TLR10. In addition, keratinocytes ex vivo display TLR1–5, TLR7, and TLR10. Accordingly, highly enriched immature LC efficiently respond to TLR2 agonists peptidoglycan and lipoteichoic acid from Gram-positive bacteria, and to dsRNA which engages TLR3. In contrast, LC do not directly sense TLR7/8 ligands and LPS from Gram-negative bacteria, which signals through TLR4. TLR engagement also results in cytokine production, with marked differences depending on the PAMP detected. TLR2 and TLR3 ligands increase IL-6 and IL-8 production, while dsRNA alone stimulates TNF- release. Strikingly, only peptidoglycan triggers IL-10 secretion, thereby suggesting a specific function in tolerance to commensal Gram-positive bacteria. However, LC do not produce IL-12p70 or type I IFNs. In conclusion, human LC are equipped with TLR that enable direct detection of PAMP from viruses and Gram-positive bacteria, subsequent phenotypic maturation, and differential cytokine production. This implies a significant role for LC in the control of skin immune responses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ V.F. was the recipient of a grant from the Fondation Marcel Mérieux. M.B. was the recipient of a grant from the Association Nationale de Recherche sur le Sida. J.V. was supported by the Association Nationale de Recherche sur le Sida, the Sidaction, and the Société Française de Dermatologie.

² Current address: Department of Dermatology, Innsbruck Medical University, Innsbruck, Austria.

³ Current address: Service de Pneumologie, Centre Hospitalier Lyon-Sud, Pierre- Bénite, France.

⁴ Address correspondence and reprint requests to Dr. Jenny Valladeau, Université Claude Bernard–Lyon I, EA3732, Centre Hospitalier Edouard Herriot, Dermatologie-Pavillon R, 69437 Lyon cedex, France. E-mail address: valladeau{at}lyon.inserm.fr

⁵ Abbreviations used in this paper: DC, dendritic cell; LC, Langerhans cell; PAMP, pathogen-associated molecular pattern; LTA, lipoteichoic acid; PGN, peptidoglycan; ODN, oligodeoxynucleotide; mDC, myeloid DC; pDC, plasmacytoid DC; rRNA, ribosomal RNA; CBA, cytometric bead array; PI, propidium iodide.

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