Langerhans cells (LC) are dendritic cells of the epidermis. They are highly specialized leukocytes that serve immunogenic and tolerogenic purposes. Here, we review some aspects of LC biology, emphasizing those areas where LC are or may turn out to be special.

The CC chemokine CCL21 is a potent chemoattractant for lymphocytes and dendritic cells in vitro. In the murine genome there are multiple copies of CCL21 encoding two CCL21 proteins that differ from each other by one amino acid at position 65 (either a serine or leucine residue). In this report, we examine the expression pattern and biological activities of both forms of CCL21. We found that although both serine and leucine forms are expressed in most tissues examined, the former was the predominant form in lymphoid organs while the latter was predominantly expressed in nonlymphoid organs. When expressed in transgenic pancreas, both forms of CCL21 were capable of inducing the formation of lymph node-like structures composed primarily of T and B cells and a few dendritic cells. Induction of lymph node-like structures by these CCL21 proteins, however, could not be reproduced in every tissue. For instance, no lymphocyte recruitment or accumulation was observed when CCL21 was overexpressed in the skin. We conclude that both forms of CCL21 protein are biologically equivalent in promoting lymphocyte recruitment to the pancreas, and that their ability to induce the formation of lymph node-like structures is dependent on the tissues in which they are expressed.

Dendritic cells are professional antigen-presenting cells that initiate primary immunity. Migration from sites of antigen uptake to lymphoid organs is crucial for the generation of immune responses. We investigated the migratory pathways specifically of epidermal Langerhans cells by tracing them from the epidermis to the draining lymph nodes. This was possible with a new monoclonal antibody, directed against murine Langerin/CD207, a type II lectin specific for Langerhans cells. In situ, resident, and activated Langerhans cells express Langerin in the epidermis and on their way through dermal lymphatic vessels. Both emigrated and trypsinization-derived Langerhans cells expressed high levels of Langerin intracellularly but reduced it upon prolonged culture periods. Sizeable numbers of Langerin+ cells were found in skin draining lymph nodes but not in mesenteric nodes. Langerin+ cells localized to the T cells areas and rarely to B cell zones. Numbers of Langerin-expressing cells increased after application of a contact sensitizer. In the steady state, Langerhans cells in the skin-draining nodes expressed maturation markers, such as 2A1 and costimulatory molecules CD86 and CD40. These molecules, CD86 and CD40, were further upregulated upon inflammatory stimuli such as contact sensitization. Thus, the novel anti-Langerin monoclonal antibody permits the unequivocal visualization of migratory Langerhans cells in the lymph nodes for the first time and thereby allows to dissect the relative immunogenic or tolerogenic contributions of Langerhans cells and other types of dendritic cells.

Inflammatory bowel disease (IBD) constituting Crohn's disease (CD) and ulcerative colitis (UC) is related to a dysregulated T cell response. CCL20 attracts memory T lymphocytes and dendritic cells. We asked whether CCL20 expression is altered in IBD. Colonic biopsies were obtained from 114 subjects with IBD, non-IBD colitis, irritable bowel syndrome, and healthy controls. CCL20 and CCR6 mRNA expression was measured by Taqman-PCR, and protein secretion from colonic explant cultures (CEC) and its regulation by TNF-alpha by ELISA. CCL20, CCR6, and Langerin were identified by immunohistochemistry and immunofluorescence. CCL20 mRNA and protein were severalfold increased in involved CD and UC but not in non-IBD colitis. TNF-alpha increased and anti-TNF-alpha decreased CCL20 release in healthy control CEC but not in involved IBD colonic specimens. CCL20 localized to follicle-associated epithelium, and CCR6 to the adjacent mantle zone of lymphoid follicles. Furthermore, abundant numbers of Langerin(+) immature dendritic cells were identified in the subepithelial space of IBD specimens. CCL20 might regulate the attraction of T lymphocytes and dendritic cells in IBD.

C-type lectins are cell surface receptors that recognize carbohydrate structures which are often part of microbial pathogens. Several of these molecules are expressed on dendritic cells and are involved in antigen uptake. Expression of C-type lectins on dendritic cells of the human skin, i.e. Langerhans cells of the epidermis and dermal dendritic cells, has been incompletely studied to date. We therefore investigated C-type lectins in situ and on dendritic cells obtained by migration from skin explants by immunofluorescence and flow cytometry. Emphasis was laid on expression patterns of DEC-205/CD205 and BDCA-2, a marker for plasmacytoid dendritic cells. Langerhans cells in situ expressed low levels of DEC-205. Expression was upregulated upon maturation in skin explant organ culture. Most dermal dendritic cells were found to be positive for DEC-205 and DC-SIGN/CD209. Few BDCA-2-expressing cells were found in most skin samples. They were located in small groups in the dermis close beneath the basement membrane. The vast majority of all types of dendritic cells in normal human skin was of immature phenotype, i.e. did not express DC-LAMP/CD208. It is concluded that normal appearing human skin harbors different subsets of dendritic cells including few scattered BDCA-2-expressing cells, presumably plasmacytoid dendritic cells, expressing variable sets of C-type lectin receptors. This may critically contribute to the capacity of the skin immune system to flexibly respond to the world of microbial pathogens.