Langerhans cells (LCs) form a network of dendritic cells in the epidermis. Epidermal TGF-b1 is a key microenvironmental signal for LC differentiation. Although recent studies have contributed to a novel view of these cells the molecular mechanism underlying TGF-b1-mediated LC differentiation and function still remains poorly defined. We used transcriptional profiling to characterize dominant acting factors that act downstream of TGF-b1 to induce LC commitment. We used retroviral over-expression studies to validate some of these factors and could provide first evidence for a functional involvement of these transcriptional regulators in LC differentiation.
In addition to its role in development, TGF-b1 has also been implicated in the maintenance of an immature LC state. In line with this we found constitutive high expression levels of miR-146a in immature LCs and could show that these levels are established via TGF-b1 mediated induction of PU.1 during LC differentiation. Interestingly, constitutive high miR-146a expression in LCs did not control myeloid/DC subset differentiation, but the ability of cells to respond to Toll like receptor (TLR) ligand mediated activation. We found high miR-146a levels to interfere with NF-kB and p38 dependent downstream signalling responses and thus the production of pro-inflammatory cytokines. Therefore high miR-146a in LCs might to increase LC resistance to activation by harmless commensal TLR ligands. Together these data encourage the rising opinion of a potential role of LCs in the induction of tolerance to environmentally derived peripheral antigens and provide additional evidence for a role of TGF-b1 in this process.