Cutting Edge: Loss of TLR2, TLR4, and TLR5 on Langerhans Cells Abolishes Bacterial Recognition

Abstract

It is unknown whether closely related epidermal dendritic cells, Langerhans cells (LCs), and dermal dendritic cells (DDCs) have unique functions. In this study, we show that human DDCs have a broad TLR expression profile, whereas human LCs have a selective impaired expression of cell surface TLR2, TLR4, and TLR5, all involved in bacterial recognition. This distinct TLR expression profile is acquired during the TGF-β1-driven development of LCs in vitro. Consequently, and in contrast to DDCs, LCs weakly respond to bacterial TLR2, TLR4, and TLR5 ligands in terms of cytokine production and maturation, as well as to whole Gram-positive and Gram-negative bacteria, whereas their responsiveness to viral TLR ligands and viruses is fully active and comparable to DDCs. Unresponsiveness of LCs to bacteria may be a mechanism that contributes to tolerance to bacterial commensals that colonize the skin.

Intradermal Delivery of TLR Agonists in a Human Explant Skin Model: Preferential Activation of Migratory Dendritic Cells by Polyribosinic-Polyribocytidylic Acid and Peptidoglycans

“…1). Strong activation by TLR-Ls was also reported for isolated monocyte- derived LCs (8,17). Of note, also overall migration rates of the skin APCs were not affected by intradermal injection of any of the tested TLR agonists.…”

“…Human epidermal LCs have been reported to express only virus-recognizing TLRs to keep them from inadvertently being activated by commensal bacteria. In contrast, DDCs express TLRs recognizing both bacteria and viruses (8). So far, the ability of TLR agonists to stimulate cutaneous DCs has mostly been tested in vitro (9).…”

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

“…This difference in cytokine secretion level was reported for IL-6 and is suspected to depend on TGF-b added to the cultures in the differentiation process of the MoLC [36,23]. Unsorted MoDC are reported strongly and weakly to produce IL-6 after activation with PGN [36,18], whereas Pam 3 CSK 4 induced equal amounts of IL-6 in these studies.…”

“…This difference in cytokine secretion level was reported for IL-6 and is suspected to depend on TGF-b added to the cultures in the differentiation process of the MoLC [36,23]. Unsorted MoDC are reported strongly and weakly to produce IL-6 after activation with PGN [36,18], whereas Pam 3 CSK 4 induced equal amounts of IL-6 in these studies. However, it seems to be likely that LC as cells that control a defined immunological area in the suprabasal keratinocyte environment can perform this task rather by paracrine cytokine communication and even lower cytokine amounts than MoDC representing DC localized in human blood.…”

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].…”