title: IL-17 suppresses immune effector functions in human papillomavirus-associated epithelial hyperplasia.
abstract: Persistent infection with high-risk human papillomaviruses (HPV) causes epithelial hyperplasia that can progress to cancer and is thought to depend on immunosuppressive mechanisms that prevent viral clearance by the host. IL-17 is a cytokine with diverse functions in host defense and in the pathology of autoimmune disorders, chronic inflammatory diseases, and cancer. We analyzed biopsies from patients with HPV-associated cervical intraepithelial neoplasia grade 2/3 and murine skin displaying HPV16 E7 protein-induced epithelial hyperplasia, which closely models hyperplasia in chronic HPV lesions. Expression of IL-17 and IL-23, a major inducer of IL-17, was elevated in both human HPV-infected and murine E7-expressing lesions. Using a skin-grafting model, we demonstrated that IL-17 in HPV16 E7 transgenic skin grafts inhibited effective host immune responses against the graft. IL-17 was produced by CD3(+) T cells, predominantly CD4(+) T cells in human, and CD4(+) and γδ T cells in mouse hyperplastic lesions. IL-23 and IL-1β, but not IL-18, induced IL-17 production in E7 transgenic skin. Together, these findings demonstrate an immunosuppressive role for IL-17 in HPV-associated epithelial hyperplasia and suggest that blocking IL-17 in persistent viral infection may promote antiviral immunity and prevent progression to cancer.
authors: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4102, Australia; and.
authors: Christina
authors: C
authors: Gosmann
authors: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4102, Australia; and.
authors: Stephen R
authors: SR
authors: Mattarollo
authors: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4102, Australia; and.
authors: Jennifer A
authors: JA
authors: Bridge
authors: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4102, Australia; and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland 4102, Australia i.frazer@uq.edu.au.
authors: Ian H
authors: IH
authors: Frazer
authors: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4102, Australia; and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland 4102, Australia.
authors: Antje
authors: A
authors: Blumenthal
mesh_terms: D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D005260:Female; D052162:Human papillomavirus 16 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000276:immunology*; D030361:Papillomavirus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: C508585:IL1B protein, human; C587672:IL1B protein, mouse; D020381:Interleukin-17; D053583:Interleukin-1beta; D053759:Interleukin-23; D050725:Papillomavirus E7 Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; C059731:oncogene protein E7, Human papillomavirus type 16