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-α 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.

Langerhans cells and viral immunity

“…Consistent with this suggestion, Waithman et al [7] formally showed that presentation of skin-derived selfantigen by lymph node-resident mature LC during the steadystate, directly led to deletional T-cell tolerance. Also consistent with immunoregulation, the TLR expression profile by LC with low expression of TLR-2 and -4 necessary for bacterial recognition results in selective unresponsiveness of LC to bacteria compared with viruses and may contribute to tolerance to bacterial commensals [8,9]. In some cases dermal DC may play the immunostimulatory role previously attributed to LC [10][11][12].…”

TLR2‐activated human langerhans cells promote Th17 polarization via IL‐1β, TGF‐β and IL‐23

“…TLR2 was previously found to be expressed by epidermal LC, CD1c 1 MoDC and CD1c 1 MoLC [23,28]. In cultures of CD1c 1 MoLC, TLR2 was treated by saturating concentrations of an antagonistic monoclonal antibody, T2.5, before stimulation by PGN.…”

Insights into Langerhans cell function from Langerhans cell ablation models

“…Second, LC transport antigen to skindraining lymph nodes (LN), which is essential to ensure interaction with rare antigen-specific naive T cells. Stimulation by a number of pathogen products in addition to pro-inflammatory cytokines induces LC activation [7][8][9]. Activated LC downregulate expression of E-cadherin, which is thought to maintain their position in the epidermis, and begin to express CC Correspondence: Daniel Kaplan e-mail: DanKaplan@umn.edu Eur.…”