Langerhans cells arise from monocytes in vivo

Abstract

Langerhans cells (LCs) are the only dendritic cells of the epidermis and constitute the first immunological barrier against pathogens and environmental insults. The factors regulating LC homeostasis remain elusive and the direct circulating LC precursor has not yet been identified in vivo. Here we report an absence of LCs in mice deficient in the receptor for colony-stimulating factor 1 (CSF-1) in steady-state conditions. Using bone marrow chimeric mice, we have established that CSF-1 receptor-deficient hematopoietic precursors failed to reconstitute the LC pool in inflamed skin. Furthermore, monocytes with high expression of the monocyte marker Gr-1 (also called Ly-6c/G) were specifically recruited to the inflamed skin, proliferated locally and differentiated into LCs. These results identify Gr-1 hi monocytes as the direct precursors for LCs in vivo and establish the importance of the CSF-1 receptor in this process.Langerhans cells (LCs) are members of a family of highly specialized antigen-presenting cells called dendritic cells (DCs). Uniquely present in the epidermis, LCs form a tight cellular network that covers the entire body surface, constituting the first immunological barrier against the external environment. LCs are well equipped to ingest antigens present in the skin and to migrate to the regional lymph node in both steady-state and inflammatory conditions 1,2 . After being activated, LCs increase their expression of major histocompatibility complex (MHC) class II and costimulatory molecules 3 and migrate to T cell areas 2 of draining lymph nodes, where they secrete T cell-attractant chemokines 4 and interact with antigen-specific T cells. Whether migrating LCs serve mainly to carry antigens to blood-derived DCs in the draining lymph nodes or whether they directly prime or tolerize antigen-specific T cells is still debated 5-8 .Given their importance in skin immunity, the mobilization of LCs to draining lymph nodes and the subsequent replacement of migrating cells by newly differentiated LCs must be tightly regulated events. Indeed, LC homeostasis is differentially regulated in quiescent and Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/ Correspondance should be addressed to M.M. (miriam.merad@mssm.edu).

Distinct Differentiation Potential of Blood Monocyte Subsets in the Lung

“…Furthermore, we demonstrate differentiation of blood monocytes into lung DC under inflammation (Fig. 6), thus extending previous reports for skin and peritoneum (7)(8)(9). In addition, these monocyte-derived lung DC were capable of reconstituting CD4 ϩ T cell priming in an immunodeficient mouse model (Fig.…”

“…Furthermore, in vivo studies also provide evidence that blood monocytes can act as precursors of M⌽ (1,5,6). More recent reports have shown that monocytes can under inflammatory conditions differentiate in vivo into conventional CD11c high DC (cDC) (7,8) and Langerhans cells (9). However, interestingly, blood monocytes seem not to contribute to the generation of splenic cDC (10 -12).…”

“…Results of adoptive transfers of fractionated murine monocytes suggest that these cells are also functionally distinct: Gr1 low monocytes were found to be recruited to resting tissues, whereas the Gr1 high monocytes shuttle between the blood and the bone marrow (BM) unless recruited to sites of inflammation (8,12). With regard to their differential fates, Gr1 high monocytes were shown in mice to differentiate into cDC and Langerhans cells under inflammation (8,9), and both Gr1 high and Gr1 low rat monocytes were reported to give rise to intestinal DC in steady state (17). However, for neither of the subsets the in vivo potential to become M⌽ has been investigated.…”

Macrophage heterogeneity and acute inflammation

“…On the other hand, neither transfer of syngeneic BM cells in mice nor transfer of cells in parabiotic mouse models has supported this interpretation and a human patient with limb transplants was found to retain donor Langerhans cells for many years (reviewed in [16]). Subsequent studies have suggested that Langerhans cells survive by self-proliferation in normal tissue and are replaced by peripheral precursors after UV ablation [34]. More recently, with a milder inflammatory response, it appears that Langerhans cells may constitute a more independent cell population, able to selfrenew without input from peripheral sources [17] (unless a more absolute failure of the tissue-resident population occurs [34]).…”

“…Subsequent studies have suggested that Langerhans cells survive by self-proliferation in normal tissue and are replaced by peripheral precursors after UV ablation [34]. More recently, with a milder inflammatory response, it appears that Langerhans cells may constitute a more independent cell population, able to selfrenew without input from peripheral sources [17] (unless a more absolute failure of the tissue-resident population occurs [34]). A similar proposition has been made for microglia in the brain [18,19], leading to the suggestion that this mechanism of self-renewal by local proliferation may occur in tissues where leukocyte traffic is more restricted.…”