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

Abstract

Langerhans cells (LCs) are a unique population of phagocytes programmed within embryonic skin to maintain tissue and immunological homeostasis at the epidermal barrier site. Unique amongst tissue-resident macrophages, LCs play roles in skin innervation and repair, while also functioning as migrating professional antigen presenting cells, a capability classically assigned to dendritic cells (DC). We currently lack insight into the molecular pathways that determine this dichotomy, when they are established, and whether precursors recruited to the adult skin niche access the same instructive signals laid downin utero. Tracking differentiation of monocyte-derived (m)LCs after destruction of embryo-derived cells in murine adult skin, we reveal intrinsic intra-epidermal heterogeneity and selection of MDP-monocytes to by-pass gene programs specifying a macrophage fate. Within the adult skin, we demonstrate that the hair follicle niche provides Notch signals that determine commitment to become resident mLCs. Using a unique human LC dataset, we show that embryo-derived (e)LCs in newborn human skin retain transcriptional evidence of their macrophage origin, but this is superseded by distinct DC-like immune modules after expansion of the eLC network. Thus, convergent differentiation of monocytes within adult skin replicates conditioning of eLC to-wards more immunogenic DC-like cells within post-natal skin.