biostudies-literatureAppios AWellcome TrustBiotechnology and Biological Sciences Research Councileadp0344https://www.ebi.ac.uk/biostudies/studies/S-EPMC7616733biostudies-literatureUnknown9(99)Langerhans cells (LCs) are distinct among phagocytes, functioning both as embryo-derived, tissue-resident macrophages in skin innervation and repair and as migrating professional antigen-presenting cells, a function classically assigned to dendritic cells (DCs). Here, we demonstrate that both intrinsic and extrinsic factors imprint this dual identity. Using ablation of embryo-derived LCs in the murine adult skin and tracking differentiation of incoming monocyte-derived replacements, we found intrinsic intraepidermal heterogeneity. We observed that ontogenically distinct monocytes give rise to LCs. Within the epidermis, Jagged-dependent activation of Notch signaling, likely within the hair follicle niche, provided an initial site of LC commitment before metabolic adaptation and survival of monocyte-derived LCs. In the human skin, embryo-derived LCs in newborns retained transcriptional evidence of their macrophage origin, but this was superseded by DC-like immune modules after postnatal expansion. Thus, adaptation to adult skin niches replicates conditioning of LC at birth, permitting repair of the embryo-derived LC network.Science immunologyConvergent evolution of monocyte differentiation in adult skin instructs Langerhans cell identity.PMC7616733109377/Z/15/ZBB/T005246/1Law MLCarvalho IBCarvalho CPolak MEPinto MMArdern-Jones MBennett CLHall NJHenderson SGentek RAppios AEmmerson ELiu ZGinhoux FTrzebanski SLovlekar SMajor CSirvent SSchroth JHenson SMDavies JVallejo AKan HYJung SfalseConvergent evolution of monocyte differentiation in adult skin instructs Langerhans cell identity.Langerhans cells (LCs) are distinct among phagocytes, functioning both as embryo-derived, tissue-resident macrophages in skin innervation and repair and as migrating professional antigen-presenting cells, a function classically assigned to dendritic cells (DCs). Here, we demonstrate that both intrinsic and extrinsic factors imprint this dual identity. Using ablation of embryo-derived LCs in the murine adult skin and tracking differentiation of incoming monocyte-derived replacements, we found intrinsic intraepidermal heterogeneity. We observed that ontogenically distinct monocytes give rise to LCs. Within the epidermis, Jagged-dependent activation of Notch signaling, likely within the hair follicle niche, provided an initial site of LC commitment before metabolic adaptation and survival of monocyte-derived LCs. In the human skin, embryo-derived LCs in newborns retained transcriptional evidence of their macrophage origin, but this was superseded by DC-like immune modules after postnatal expansion. Thus, adaptation to adult skin niches replicates conditioning of LC at birth, permitting repair of the embryo-derived LC network.2024-01-01T00:00:00Z2024 Sep2025-04-04T00:08:47.076Z2025-04-04T00:08:47.076ZS-EPMC76167333924105710.1126/sciimmunol.adp0344