title: HPV16-E7 expression in squamous epithelium creates a local immune suppressive environment via CCL2- and CCL5- mediated recruitment of mast cells.
abstract: Human Papillomavirus (HPV) 16 E7 protein promotes the transformation of HPV infected epithelium to malignancy. Here, we use a murine model in which the E7 protein of HPV16 is expressed as a transgene in epithelium to show that mast cells are recruited to the basal layer of E7-expressing epithelium, and that this recruitment is dependent on the epithelial hyperproliferation induced by E7 by inactivating Rb dependent cell cycle regulation. E7 induced epithelial hyperplasia is associated with increased epidermal secretion of CCL2 and CCL5 chemokines, which attract mast cells to the skin. Mast cells in E7 transgenic skin, in contrast to those in non-transgenic skin, exhibit degranulation. Notably, we found that resident mast cells in E7 transgenic skin cause local immune suppression as evidenced by tolerance of E7 transgenic skin grafts when mast cells are present compared to the rejection of mast cell-deficient E7 grafts in otherwise competent hosts. Thus, our findings suggest that mast cells, recruited towards CCL2 and CCL5 expressed by epithelium induced to proliferate by E7, may contribute to an immunosuppressive environment that enables the persistence of HPV E7 protein induced pre-cancerous lesions.
authors.affiliation: The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Bergot
authors.affiliation: The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Neill
authors.initials: N
authors.lastname: Ford
authors.affiliation: The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Leggatt
authors.affiliation: The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: James W
authors.initials: JW
authors.lastname: Wells
authors.affiliation: The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Frazer
authors.affiliation: Division of Human Immunology, Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors.forename: Michele A
authors.initials: MA
authors.lastname: Grimbaldeston
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D018932:Chemokine CCL2 / Q000276:immunology*; D018946:Chemokine CCL5 / Q000276:immunology*; D004777:Environment; D004848:Epithelium / Q000821:virology*; D006801:Humans; D008407:Mast Cells / Q000821:virology*; D008810:Mice, Inbred C57BL; D050725:Papillomavirus E7 Proteins / Q000378:metabolism*; D012867:Skin / Q000821:virology
chemical_list: D018932:Chemokine CCL2; D018946:Chemokine CCL5; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16