Portal de Periódicos da CAPES

Dendritic cells in the skin and mucosa: what’s new

2001; Wiley; Volume: 15; Issue: 2 Linguagem: Inglês

10.1046/j.1468-3083.2001.00224.x

1468-3083

Paolo Romagnoli,

Cancer Immunotherapy and Biomarkers

In this issue Holikovàet al. review recent pieces of evidence on Langerhans and other dendritic cells. These cells have moved to the forefront of immunology in that they are shown to be responsible for the activation of CD4+ T-cell-dependent responses; furthermore, dendritic cells have been shown to stimulate CD8+ T-cell-dependent responses, even independently of CD4+ T-cell help.1 The impact of dendritic cells on the immune response does not seem to be limited to the T-lymphocyte branch, as they have been shown recently to promote the differentiation of plasma cells from B lymphocytes even in the absence of T-cell help2 and to promote plasmablast survival.3 Recent evidence recapitulated by Holikovàet al. indicates that dendritic cells are instrumental in driving helper T cells towards a definite type of response, whether Th1, Th2 or anergy, and that this in turn depends on the cytokine cocktail to which dendritic cells are exposed upon uptake of antigens or haptens and undergoing ‘maturation’. This last term should be used with caution, as the terms immature and mature used with reference to cells of dendritic lineage (see Holikovàet al. for more detail) are useful inasmuch they recall that these two stages are reached in sequence; however, they are misleading inasmuch that they overlook that the transition between them is regulated by extrinsic clues and is indeed a process of differentiation marked by deep, apparently irreversible changes in phenotype that follow relevant changes in gene expression. Both surrounding cells (including keratinocytes, as recently reviewed4) and dendritic cells themselves can contribute to the cocktail of cytokines controlling dendritic cell differentiation and function; as indicated by Holikovàet al. the cytokines secreted by dendritic cells can depend in part on the type of not-self molecule to which they have been exposed. The evidence reiterated by Holikovàet al. can be expected to influence the perception of how immune system cells organize themselves into an integrated network and on the procedures that can be envisaged to manipulate immune responses, especially as dendritic cells have already begun to be exploited for active immunization against cancer. Research is rapidly expanding in the field of dendritic cell generation in vitro, providing critical information on the physiological stimuli that lead to differentiation of these cells from their precursors. However, the field is far from settled: the stages of immature and mature dendritic cells seem to be reached from more than one precursor and by more than one independent pathway (as recalled by Holikovàet al. and analysed in a recent review4), and what exactly happens in vivo awaits to be discovered. Also, in vitro studies cannot appreciate the role of innervation, which can greatly affect the differentiation and function of dendritic cells at least in the epidermis.5,6 Most studies on the differentiation of dendritic cells in vitro consider them as a single bunch; however, there are several types of these cells, among which Langerhans cells deserve special attention – first of all by skin physiologists and clinicians. Langerhans cells are prototype immature dendritic cells, which can take up antigens but not stimulate lymphocytes; however, they bear specific immunophenotypical and structural markers that hint to peculiarities in their differentiation pathway and function, as compared with other immature dendritic cells; these peculiarities still await to be clarified. Neurotransmitters, besides cytokines, can provide for relevant information for the differentiation and function of Langerhans cells, as these cells express receptors for several neurotransmitters.5 Neurotransmitters (at least calcitonin gene-related peptide) can affect Langerhans cell differentiation and function also through dermal intermediate cells, in particular mast cells, giving rise to a loop involving both neurotransmitters and cytokines.6 These last findings cast some light on the correlations among skin, immune cells and the nerve system; such correlations are known to occur because their effects are manifest in the clinics, but they exploit mechanisms that have been elusive until now and still require more research to be understood in full and hence manipulated purposefully. The skin contains both epidermal Langerhans cells and dermal dendritic cells;7 the same applies to mucosae, at least those lined by stratified squamous epithelium. Dermal dendritic cells share features with macrophages and have been shown to be capable of promoting sensitization at least as efficiently as Langerhans cells. Langerhans cells represent a noticeable number of cells, probably overshooting 109 for the whole body (see Holikovàet al. for figures on the number density of these cells), and are renewed continuously; a major issue that has received little attention until now is why does skin need Langerhans cells at all, given dermal cells can bear sensitization against exogenous molecules as well. One possible explanation for the presence of Langerhans cells in the epidermis and mucosae, that comes out of Holikovàet al., is that these cells are a first line defence against bacterial invasion, because they are especially well equipped to take up and present bacterial antigens. In normal conditions, bacteria and their water soluble products find in the horny layer and the epidermal lipid barrier a valuable obstacle to penetrate epidermis. In intact skin Langerhans cells would promptly activate responses against lipid bacterial antigens by way of CD1 molecules and, in case of a drop in epidermal barrier and in mucosae (that have no epidermal barrier equivalent), they would do the same against polysaccharide bacterial antigens by way of other molecules. The dermis, or mucosa lamina propria, would also be reached in the latter cases and contain plenty of antigen-presenting cells that remain in place even upon removing the epithelium; however, these cells may prove much less efficient than Langerhans cells against, at least, some bacterial antigens because of the virtual lack of CD1a (not of other CD1) molecules and lack of langerin and galectin-3 molecules (the role of which molecules has been recognized recently and is highlighted in Holikovàet al.). Another possible reason for the presence of Langerhans cells in the epidermis is their peculiar efficiency in promoting cell-mediated immune responses against very low antigen load. Evidence has been presented that normal, sensitizing doses of haptens elicit a response mediated by dermal dendritic cells, whereas Langerhans cells are disturbed in structure and impaired in function in the same conditions; on the contrary, very low doses of haptens are unable to elicit sensitization through dermal dendritic cells and the response to these low doses depends strictly on Langerhans cells.8,9 These findings challenge the role of Langerhans cells in contact sensitization against environmental haptens and antigens, which usually reach the skin at relatively high doses, and draw attention to the part played by these cells in conditions of low antigen load, which may be represented by early phases of some bacterial and most viral infections and by early stages of cancer development. It has been known for several years that Langerhans cells can take up cancer antigens from within the epidermis;10 more recently, it has been proposed that selective damage of these cells, over other types of dendritic cells, might explain the higher susceptibility to skin cancer in patients treated with cyclosporin A for long periods of time, whereas other types of malignancies occur as frequently in these patients as in those treated with other immunosuppressant regimens.11 The role of Langerhans cells as Trojan horses for the human immunodeficiency virus might represent the exploitation by this virus of a natural propensity of Langerhans cells to take up viruses as antigens and to contact lymphocytes thereafter.12 Papers such as those by Holikovàet al. present us with much needed studies on Langerhans cells. They also remind us that long after Langerhans presented these cells to the scientific community and Hashimoto and Tarnowski recognized them as a cell lineage that migrates into the epidermis continuously throughout life and is correlated with macrophages, Langerhans cells and their companion dendritic cells in the lamina propria still challenge physiologists and clinicians as to their peculiar features and roles in physiology and pathology. They give reason for continuous generation of new data in order to highlight and understand the peculiar position of these cells within the dendritic cell family. Research was supported by the Italian Ministry of Universities and Research in Science and Technology, the Italian National Research Council, the University of Florence and the Alexander von Humboldt Foundation.