title: Human Langerhans cells express a specific TLR profile and differentially respond to viruses and Gram-positive bacteria.
abstract: 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-alpha 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.
authors.affiliation: Laboratory for Immunological Research, Schering-Plough, Dardilly, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Flacher
authors.forename: Marielle
authors.initials: M
authors.lastname: Bouschbacher
authors.forename: Estelle
authors.initials: E
authors.lastname: Verronèse
authors.forename: Catherine
authors.initials: C
authors.lastname: Massacrier
authors.forename: Vanja
authors.initials: V
authors.lastname: Sisirak
authors.forename: Odile
authors.initials: O
authors.lastname: Berthier-Vergnes
authors.forename: Blandine
authors.initials: B
authors.lastname: de Saint-Vis
authors.forename: Christophe
authors.initials: C
authors.lastname: Caux
authors.forename: Colette
authors.initials: C
authors.lastname: Dezutter-Dambuyant
authors.forename: Serge
authors.initials: S
authors.lastname: Lebecque
authors.forename: Jenny
authors.initials: J
authors.lastname: Valladeau
mesh_terms: D006094:Gram-Positive Bacteria / Q000276:immunology*; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D007801:Langerhans Cells / Q000276:immunology* / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000166:cytology / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D014780:Viruses / Q000276:immunology*
chemical_list: D015850:Interleukin-6; D016209:Interleukin-8; D012330:RNA, Double-Stranded; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha