Revisiting the tolerogenicity of epidermal Langerhans cells

Langerhans cells (LC) are unique members of the dendritic cell (DC) family residing in the epidermis of skin and mucosa. Specific autocrine and environmental factors shape the biology of LC, such as TGF-beta1, IL-10, vitamin D(3), UV light or neuropeptides, which are required for LC development but also influence their capacity to induce immunity or tolerance. Both, immunogenic and tolerogenic functions require antigen transport from the skin to the draining lymph nodes, but the LC maturation grade directs the differential outcome. In this review, we recapitulate early indications for LC tolerogenicity and oppose them to more recent findings with gene-targeted mice, which dramatically challenged some of the early results. The newly discovered Langerin(+) dermal DC subset (DDC) seems to be responsible also for many tolerogenic effects that were initially attributed to steady state migratory LC. Transfer of antigens from LC to other DC subsets as well as transport of HIV are discussed as part of the complex interactions between LC and other cells or as mechanisms of immune evasion. Finally, the first clinical trials on allergy therapies targeting skin DC in the steady state are mentioned as they may open the door to curative tolerogenic therapies.