Notch-Mediated Generation of Monocyte-Derived Langerhans Cells: Phenotype and Function

Langerhans cells (LCs) in the skin are a first line of defense against pathogens but also play an essential role in skin homeostasis. Their exclusive expression of the C-type lectin receptor Langerin makes them prominent candidates for immunotherapy. For vaccine testing, an easily accessible cell platform would be desirable as an alternative to the time-consuming purification of LCs from human skin. Here, we present such a model and demonstrate that monocytes in the presence of GM-CSF, TGF-beta 1, and the Notch ligand DLL4 differentiate within 3 days into CD1a(+)Langerin(+) cells containing Birbeck granules. RNA sequencing of these monocyte-derived LCs (moLCs) confirmed gene expression of LC-related molecules, pattern recognition receptors, and enhanced expression of genes involved in the antigen-presenting machinery. On the protein level, moLCs showed low expression of costimulatory molecules but prominent expression of C-type lectin receptors. MoLCs can be matured, secrete IL-12p70 and TNF-alpha, and stimulate proliferation and cytokine production in allogeneic CD4(+) and CD8(+) T cells. In regard to vaccine testing, a recently characterized glycomimetic Langerin ligand conjugated to liposomes demonstrated specific and fast internalization into moLCs. Hence, these short-term in vitro-generated moLCs represent an interesting tool to screen LC-based vaccines in the future.

Automated summary

Langerhans cells in the skin, critical for immune response and skin homeostasis, can be generated from monocytes with specific cytokines and ligands. These monocyte-derived LCs show potential for vaccine testing and can be an effective tool for future research.