Langerhans cell (LC) proliferation mediates neonatal development,homeostasis, and inflammation-associated expansion of the epidermal LC network

Most tissues develop from stem cells and precursors that undergo differentiation as their proliferative potential decreases. Mature differentiated cells rarely proliferate and are replaced at the end of their life by new cells derived from precursors. Langerhans cells (LCs) of the epidermis, although of myeloid origin, were shown to renew in tissues independently from the bone marrow, suggesting the existence of a dermal or epidermal progenitor. We investigated the mechanisms involved in LC development and homeostasis. We observed that a single wave of LC precursors was recruited in the epidermis of mice around embryonic day 18 and acquired a dendritic morphology, major histocompatibility complex II, CD11c, and langerin expression immediately after birth. Langerin⁺ cells then undergo a massive burst of proliferation between postnatal day 2 (P2) and P7, expanding their numbers by 10–20-fold. After the first week of life, we observed low-level proliferation of langerin⁺ cells within the epidermis. However, in a mouse model of atopic dermatitis (AD), a keratinocyte signal triggered increased epidermal LC proliferation. Similar findings were observed in epidermis from human patients with AD. Therefore, proliferation of differentiated resident cells represents an alternative pathway for development in the newborn, homeostasis, and expansion in adults of selected myeloid cell populations such as LCs. This mechanism may be relevant in locations where leukocyte trafficking is limited.Current data indicate that many macrophage subsets and most DCs in nonlymphoid tissues and in the secondary lymphoid organs of mice originate and are renewed from bone-marrow hematopoietic stem cell–derived progenitors with myeloid-restricted differentiation potential (Fogg et al., 2006; Liu et al., 2009). However, exceptions must exist to this major pathway of macrophage and DC generation, because Langerhans cells (LCs) and microglia remain of host origin after syngeneic bone marrow transplant (Merad et al., 2002; Ajami et al., 2007; Mildner et al., 2007), and LCs remain of donor origin after a limb graft (Kanitakis et al., 2004). Epidermal LCs have been shown to be a cycling population (Giacometti and Montagna, 1967; Czernielewski et al., 1985; Czernielewski and Demarchez, 1987). LC precursors were proposed to reside in the dermis (Larregina et al., 2001) or in the hair follicle (Gilliam et al., 1998), and cells with features of proliferating LC precursors have been found in fetal and newborn skin (Elbe et al., 1989; Chang-Rodriguez et al., 2005). On the other hand, monocytes can give rise to LC-like cells in vitro (Geissmann et al., 1998; Mohamadzadeh et al., 2001), and LCs can be replaced by bone marrow–derived cells in a selected experimental setting, i.e., after allogeneic bone marrow transplant, UV light irradiation, and conditional genetic ablation (Katz et al., 1979; Frelinger and Frelinger, 1980; Merad et al., 2002; Bennett et al., 2005). The nature of the endogenous LC precursor is thus unclear.LC development is controlled by M-CSF receptor and TGF-β1 (Borkowski et al., 1996; Ginhoux et al., 2006; Kaplan et al., 2007), but the LC precursor is particularly enigmatic because, in contrast to most organs, migration of leukocytes into the epidermis, as well as the brain, is rarely observed in a steady state; when such migration is observed, it is typically associated with inflammation. The mechanisms by which LCs develop and are renewed may differ from those involved in organs where hematopoietic cells circulate constantly, such as the spleen, liver, or lung. Although the roles of epidermal LCs remain controversial, recent evidence indicates a role as scavengers for viruses such as HIV-1 (de Witte et al., 2007) and possibly for carcinogens (Strid et al., 2008), as well as their role in promoting and regulating T cell–mediated immune responses (Bennett et al., 2007; Stoitzner et al., 2008; Elentner et al., 2009; Vesely et al., 2009). Understanding the mechanisms that control the development and homeostasis of DCs and macrophages in the skin or brain is thus of importance in understanding the pathophysiology of inflammation in these organs. In this study, we investigated the development of the LC network of the epidermis, and how it is maintained in a steady state and during epidermal inflammation.