A model of impaired Langerhans cell maturation associated with HPV induced epithelial hyperplasia
Zewen K. Tuong,
Samuel W. Lukowski,
Quan H. Nguyen,
Janin Chandra,
Chenhao Zhou,
Kevin Gillinder,
Abate A. Bashaw,
John R. Ferdinand,
Benjamin J. Stewart,
Siok Min Teoh,
Sarah J. Hanson,
Katharina Devitt,
Menna R. Clatworthy,
Joseph E. Powell,
Ian H. Frazer
Affiliations
Zewen K. Tuong
The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia; Molecular Immunity Unit, University of Cambridge Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UK; Corresponding author
Samuel W. Lukowski
Australia Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia
Quan H. Nguyen
Australia Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia
Janin Chandra
The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia
Chenhao Zhou
The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia
Kevin Gillinder
The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia
Abate A. Bashaw
The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia
John R. Ferdinand
Molecular Immunity Unit, University of Cambridge Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UK
Benjamin J. Stewart
Molecular Immunity Unit, University of Cambridge Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UK
Siok Min Teoh
The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia
Sarah J. Hanson
The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia
Katharina Devitt
The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia
Menna R. Clatworthy
Molecular Immunity Unit, University of Cambridge Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UK; Wellcome Trust Sanger Institute, Hinxton, UK
Joseph E. Powell
Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; Corresponding author
Ian H. Frazer
The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia; Corresponding author
Summary: Langerhans cells (LC) are skin-resident antigen-presenting cells that regulate immune responses to epithelial microorganisms. Human papillomavirus (HPV) infection can promote malignant epithelial transformation. As LCs are considered important for controlling HPV infection, we compared the transcriptome of murine LCs from skin transformed by K14E7 oncoprotein and from healthy skin. We identified transcriptome heterogeneity at the single cell level amongst LCs in normal skin, associated with ontogeny, cell cycle, and maturation. We identified a balanced co-existence of immune-stimulatory and immune-inhibitory LC cell states in normal skin that was significantly disturbed in HPV16 E7-transformed skin. Hyperplastic skin was depleted of immune-stimulatory LCs and enriched for LCs with an immune-inhibitory gene signature, and LC-keratinocyte crosstalk was dysregulated. We identified reduced expression of 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.
