Convergent evolution of monocyte differentiation in adult skin permits repair of the Langerhans cell network

• Published in: bioRxiv
• Main Authors: Appios, Anna, Davies, James, Sirvent, Sofia, Henderson, Stephen, Trzebanski, Sebastien, Schroth, Johannes, Law, Morven L, Ines Boal Carvalho, Howard Yuan-Hao Kan, Major, Christina, Vallejo, Andres, Hall, Nigel J, Ardern-Jones, Michael, Henson, Sian M, Emmerson, Elaine, Jung, Steffen, Polak, Marta E, Bennett, Clare L
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 15.11.2023
• Subjects: Antigen-presenting cells; Dendritic cells; Homeostasis; Immunogenicity; Innervation; Langerhans cells; Macrophages; Monocytes; Phagocytes; Skin
• DOI: 10.1101/2023.11.13.566862

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 down in 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embryo-derived (e)LCs in newborn human skin retain transcriptional evidence of their macrophage origin, but this is superseded by distinct DC-like immune modules after expansion of the eLC network.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 towards more immunogenic DC-like cells within post-natal skin.Competing Interest StatementMEP is currently employed at Johnson and Johnson Innovative Medicine. Johnson and Johnson Innovative Medicine or any of employees/stakeholders have not been involved in any part or aspect of the project or manuscript.