Convergent evolution of monocyte differentiation in adult skin instructs Langerhans cell identity

Abstract Langerhans cells (LCs) maintain tissue and immunological homeostasis at the epidermal barrier site. They are unique among phagocytes in functioning both as embryo-derived, tissue-resident macrophages that influence skin innervation and repair, and as migrating professional antigen presenting cells, a capability classically assigned to dendritic cells (DC). Here we report the mechanisms that determine this dual identity. Using ablation of embryo-derived LCs in murine adult skin and tracked differentiation of incoming monocyte-derived replacements, we reveal intrinsic intra-epidermal heterogeneity. Macrophage-dendritic cell precursors are selected for survival in the skin environment, by-passing gene programs that specify a macrophage fate. We demonstrate that the hair follicle niche provides Notch signals that impose LC identity. In human skin, we show that embryo-derived (e)LCs in newborns retain transcriptional evidence of their macrophage origin, but this is superseded by distinct DC-like immune modules after expansion of the eLC network. Thus, cellular adaptation to the adult skin niche replicates conditioning of eLC, instructing DC-like programmes within macrophages.