Abstract
Langerhans cells (LC) are skin-resident antigen-presenting cells that regulate immune responses to epithelial commensal and pathogenic microorganisms. Infection of skin by human papillomavirus (HPV) is commonly persistant and can promote malignant epithelial transformation. As LCs are considered important in control of HPV infection, we compared the transcriptome of LCs from skin transformed by the oncogenic E7 protein of HPV16 and from healthy skin. We identified transcriptome heterogeneity at the single cell level amongst LCs in normal mouse skin, associated with cell ontogeny, cell cycle activity, and maturation. We identified a balanced co-existence of immune-stimulatory and immune-inhibitory LC cell states in normal skin that was signficantly disturbed in HPV16 E7-expressing hyperproliferative murine skin. Hyperplastic skin was depleted of immune-stimulatory LCs, and enriched for LCs with an immune-inhibitory gene signature, and LC-keratinocyte cross-talk was dysregulated. We identified reduced expression of the CSF1R ligand interleukin (IL)-34, a critical molecule for LC homeostasis. Enrichment of an immune-inhibitory LC gene signature and reduced levels of epithelial IL-34 were also found in human HPV-associated cervical epithelial cancers. HPV16 E7 transgenic hyperplastic murine skin thus provides a robust model to investigate interventions to overcome impaired LC maturation induced by epithelial proliferation in HPV associated cancer.
Highlights
Langerhans cells (LCs) are an important subset of antigen-presenting cells (APCs) in cutaneous and mucosal epidermis, sharing both macrophage and dendritic cell (DC) phenotype and function, and regulating multiple aspects of barrier immunity (Doebel et al, 2017)
The ontogeny of LCs has been studied in mice; LCs in cutaneous and mucosal tissues can arise from three sources: either yolk sac (YS)-derived precursors, embryonic fetal liver progenitors (FLP), or hematopoietic stem cell (HSC)-derived monocyte or DC precursors from the bone marrow (Hovav, 2018)
We show that murine epithelial LCs can be categorized through transcriptomic analysis into groups with differing molecular genotypes likely to correlate with different functional phenotypes, and further show that hyperproliferative epithelium is associated with alterations in LC genotype that may explain poor immune responses to viral proteins expressed in hyperproliferative epithelium characteristic to Human papillomavirus (HPV) transformed epithelium
Summary
Langerhans cells (LCs) are an important subset of antigen-presenting cells (APCs) in cutaneous and mucosal epidermis, sharing both macrophage and dendritic cell (DC) phenotype and function, and regulating multiple aspects of barrier immunity (Doebel et al, 2017). LCs are distinct from CD11c+ CD1a epidermal DCs (Bertram et al, 2019). Despite these differences in origin, steady-state mucosal and cutaneous LCs express similar surface markers and are transcriptionally similar. All LCs express CD11b, CD11c, MHCII, Langerin (CD207) and EpCAM, and share common-gene expression patterns that are distinct from other tissue-resident APC populations, and are thought to be relatively homogeneous within their respective tissues (Capucha et al, 2015; Hovav, 2018; Ferrer et al, 2019). Recent fate-mapping studies have shown that long-lived monocyte-derived LCs are transcriptionally virtually indistinguishable from embryonically seeded LCs after resolution of the inflammation (Ferrer et al, 2019)
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