Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16- Human Blood Monocytes in Serum-Free Condition

• Published in: The Journal of immunology (1950) 2016-05, Vol.196 (9), p.3716-3728
• Main Authors: Picarda, Gaëlle, Chéneau, Coraline, Humbert, Jean-Marc, Bériou, Gaëlle, Pilet, Paul, Martin, Jérôme, Duteille, Franck, Perrot, Pierre, Bellier-Waast, Frédérique, Heslan, Michèle, Haspot, Fabienne, Guillon, Fabien, Josien, Regis, Halary, Franck Albert
• Format: Article
• Language: English
• Subjects: Antigens, Neoplasm - metabolism; Blood Cells - physiology; Cell Adhesion Molecules - metabolism; Cell Differentiation; Cells, Cultured; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Humans; Isoantigens - immunology; Keratinocytes - physiology; Langerhans Cells - immunology; Lipopolysaccharide Receptors - metabolism; Lymphocyte Activation; Monocytes - physiology; Proto-Oncogene Proteins - metabolism; Receptor Protein-Tyrosine Kinases - metabolism; Receptors, IgG - metabolism; Self Tolerance; T-Lymphocytes - immunology; Transforming Growth Factor beta1 - metabolism; Ultraviolet Rays
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1501304

Langerhans cells (LCs) are epithelial APCs that sense danger signals and in turn trigger specific immune responses. In steady-state, they participate in the maintenance of peripheral tolerance to self-antigens whereas under inflammation LCs efficiently trigger immune responses in secondary lymphoid organs. It has been demonstrated in mice that LC-deprived epithelia are rapidly replenished by short half-life langerin-expressing monocyte-derived LCs (MDLCs). These surrogate LCs are thought to be progressively replaced by langerin(high) LCs arising from self-renewing epithelial precursors of hematopoietic origin. How LCs arise from blood monocytes is not fully understood. Hence, we sought to characterize key factors that induce differentiation of langerin(high)-expressing monocyte-derived Langerhans-like cells. We identified GM-CSF and TGF-β1 as key cytokines to generate langerin(high)-expressing cells but only in serum-free conditions. These cells were shown to express the LC-specific TROP-2 and Axl surface markers and contained Birbeck granules. Surprisingly, E-cadherin was not spontaneously expressed by these cells but required a direct contact with keratinocytes to be stably induced. MDLCs induced stronger allogeneic T cell proliferations but released low amounts of inflammatory cytokines upon TLR stimulation compared with donor-paired monocyte-derived dendritic cells. Immature langerin(high) MDLCs were responsive to MIP-3β/CCL20 and CTAC/CCL27 chemokine stimulations. Finally, we demonstrated that those cells behaved as bona fide LCs when inserted in a three-dimensional rebuilt epithelium by becoming activated upon TLR or UV light stimulations. Collectively, these results prompt us to propose these langerin(high) MDLCs as a relevant model to address LC biology-related questions.