Homeostasis of Langerhans and dendritic cells in health and disease

Abstract

Dendritic Cells (DC) play a pivotal role in both the initiation of immunity and its regulation through tolerance induction. They represent potential targets or tools of therapy in autoimmunity, allergy, cancer, and transplant medicine. Despite recent progress in mapping tissue DC subsets in human, their ontogeny and mechanisms of homeostasis remain elusive. The conventional view is that maintenance of tissue DC and macrophages is dependent on constant replenishment from circulating monocyte precursors. This concept was derived from in vitro data and mouse models under perturbed conditions. While these observations may reflect events in inflammation, studies in murine steady-state biology have challenged this, with data indicating at least three ways in which DC may persist independently of monocytes: 1, tissue DC are replaced by non-monocyte, blood-borne precursors; 2, embryological cells seed tissues and persist in adulthood; 3, DC, or their immediate precursors, self-renew in tissues. These mechanisms may not be mutually exclusive. Although much has been gained from the study of DC kinetics in human transplant, these conditions are, at least in part, inflammatory. To understand the steady-state homeostasis of DC and epidermal Langerhans cells (LC) in human tissues, a number of approaches were taken. Firstly, a comprehensive ‘DC profile’ of normal human tissues was developed, starting with detailed characterization of DC, monocyte and macrophage populations in human peripheral blood (PB) and skin. This lead to the identification of new DC subsets in peripheral tissue. Cells with DC precursor potential were then sought, through analysis of their growth factor receptor expression and ability to enter into cell cycle. Correlative data was gathered to suggest relationships between potential blood borne DC precursors and skin APC. The CD34+ haematopoietic compartment was examined to identify potential DC progenitors. The granulocyte/macrophage progenitor (GMP) and a more recently described multilymphoid progenitor (MLP) were identified and shown also to be present in PB. CD34+ cells were identified in peripheral tissue. While cell and gene knockout experiments have significantly advanced understanding of murine DC, these experiments are not possible in human. The second approach was therefore to undertake a search for subjects with spontaneous DC or monocyte deficiencies. Two novel syndromes were identified; Dendritic Cell, Monocyte, B and NK Lymphoid (DCML) deficiency (4 subjects) and autosomal recessive IRF8 deficiency (1 subject). In both cases, severe depletion of peripheral blood monocyte and DC subsets was associated with absence of tissue DC but preservation of LC and some tissue macrophages. Examination of CD34+ stem cell compartments revealed distinct stem cell defects resulting in loss of MLP and depletion of GMP in DCML deficiency, but accumulation of these subsets in IRF8 deficiency. As predicted by mouse models, DC deficiency was associated with a reduction in circulating regulatory T cells, in the context of elevated Flt3-ligand. Finally, lesions of Langerhans Cell Histiocytosis (LCH), a histiocytic disorder presenting with pathological accumulation of langerin+ DC in tissues, were studied. Analysis of langerin distribution in normal skin and lung identified a langerin+ DC, independent of LC. In keeping with in vitro culture data, preliminary observations show that langerin may be up-regulated on mDC in inflammatory conditions. These data suggest that langerin expression in LCH lesions may reflect its upregulation, rather than determine the LC origin of LCH cells. A variety of techniques have been used to explore DC in normal tissue, novel syndromes of DC deficiency and Langerhans cell histiocytosis. These studies provide new insights into the ontogeny and homeostasis of human DC and LC.