title: Distinct molecular signature of human skin Langerhans cells denotes critical differences in cutaneous dendritic cell immune regulation.
abstract: Langerhans cells (LCs) are professional antigen-presenting cells (APCs) residing in the epidermis. Despite their high potential to activate T lymphocytes, current understanding of human LC biology is limited. Genome-wide comparison of the transcriptional profiles of human skin migratory CD1a+ LCs and CD11c+ dermal dendritic cells (DDCs) demonstrated significant differences between these "dendritic cell (DC)" types, including preferential expression of 625 genes (P<0.05) in LC and 914 genes (P<0.05) in DDC. Analysis of the temporal regulation of molecular networks activated after stimulation with tumor necrosis factor-α (TNF-α) confirmed the unique molecular signature of LCs. Although LCs conformed to the phenotype of professional APC, inflammatory signaling activated primarily genes associated with cellular metabolism and mitochondrial activation (e.g., CYB561 and MRPS35), cell membrane re-organization, and antigen acquisition and degradation (CAV1 and PSMD14; P<0.05-P<0.0001). Conversely, TNF-α induced classical activation in DDCs with early downregulation of surface receptors (mannose receptor-1 (MRC1) and C-type lectins), and subsequent upregulation of cytokines, chemokines (IL1a, IL1b, and CCL18), and matrix metalloproteinases (MMP1, MMP3, and MMP9; P<0.05-P<0.0001). Functional interference of caveolin abrogated LCs superior ability to cross-present antigens to CD8+ T lymphocytes, highlighting the importance of these networks to biological function. Taken together, these observations support the idea of distinct biological roles of cutaneous DC types.
authors.affiliation: Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK. Electronic address: m.e.polak@soton.ac.uk.
authors.forename: Marta E
authors.initials: ME
authors.lastname: Polak
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Thirdborough
authors.affiliation: Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Chuin Y
authors.initials: CY
authors.lastname: Ung
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Elliott
authors.affiliation: Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Eugene
authors.initials: E
authors.lastname: Healy
authors.affiliation: Systems Immunology Group, Division of Genetics and Genomics, The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Scotland, UK.
authors.forename: Tom C
authors.initials: TC
authors.lastname: Freeman
authors.affiliation: Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Ardern-Jones
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology*; D018949:Antigens, CD1 / Q000276:immunology / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D051242:Caveolin 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D020405:Dermis / Q000166:cytology / Q000276:immunology; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007801:Langerhans Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D059467:Transcriptome
chemical_list: D018949:Antigens, CD1; C495540:CAV1 protein, human; D039521:CD11c Antigen; C419393:CD1a antigen; D051242:Caveolin 1