title: Indoleamine 2,3-dioxygenase activity contributes to local immune suppression in the skin expressing human papillomavirus oncoprotein e7.
abstract: Chronic infection of anogenital epithelium with human papillomavirus (HPV) promotes development of cancer. Many pathogens evoke immunosuppressive mechanisms to enable persistent infection. We have previously shown that grafted skin expressing HPV16 E7 oncoprotein from a keratin-14 promoter (K14E7) is not rejected by a syngeneic, immunocompetent host. In this study we show that indoleamine 2,3-dioxygenase (IDO) 1, an IFN-γ-inducible immunoregulatory molecule, is more highly expressed by langerin(-ve) dermal dendritic cells (DCs) from K14E7 skin than nontransgenic control skin. Furthermore, inhibiting IDO activity using 1-methyl-dl-tryptophan (1-D/L-MT) promotes K14E7 skin graft rejection. Increased IDO1 expression and activity in K14E7 skin requires IFN-γ and invariant natural killer T (iNKT) cells, both of which have been shown to negatively regulate T-cell effector function and suppress K14E7 graft rejection. Furthermore, DCs from K14E7 skin express higher levels of IFN-γ receptor (IFN-γR) than DCs from control skin. K14E7 transgenic skin recruits significantly higher numbers of DCs, independent of IFN-γ and IFN-γR expression. Consistent with these observations in a murine model, we found higher expression of IDO1 and IFN-γ but not IDO2 in the cervical epithelium of patients with HPV-associated cervical intraepithelial neoplasia (CIN) 2/3. Our data support a hypothesis that induction of IDO1 in HPV-infected skin contributes to evasion of host immunity.
authors: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors: Deepak
authors: D
authors: Mittal
authors: Kidney Research Laboratory, Queensland Health/Queensland Institute of Medical Research, Brisbane,Queensland, Australia.
authors: Andrew J
authors: AJ
authors: Kassianos
authors: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors: Lee S
authors: LS
authors: Tran
authors: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors: Anne-Sophie
authors: AS
authors: Bergot
authors: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors: Christine
authors: C
authors: Gosmann
authors: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors: Janin
authors: J
authors: Hofmann
authors: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia; Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland, Australia.
authors: Antje
authors: A
authors: Blumenthal
authors: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors: Graham R
authors: GR
authors: Leggatt
authors: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. Electronic address: i.frazer@uq.edu.au.
authors: Ian H
authors: IH
authors: Frazer
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology / Q000821:virology*; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D053537:Keratin-17 / Q000235:genetics; D037181:Lectins, C-Type / Q000378:metabolism; D037241:Mannose-Binding Lectins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000276:immunology; D050725:Papillomavirus E7 Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017471:Receptors, Interferon / Q000378:metabolism; D012867:Skin / Q000166:cytology; D016038:Skin Transplantation; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology; D002583:Uterine Cervical Neoplasms / Q000378:metabolism; D002578:Uterine Cervical Dysplasia / Q000378:metabolism; D000096743:Interferon gamma Receptor
chemical_list: D000954:Antigens, Surface; D039521:CD11c Antigen; D007166:Immunosuppressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma; D053537:Keratin-17; D037181:Lectins, C-Type; D037241:Mannose-Binding Lectins; D050725:Papillomavirus E7 Proteins; D017471:Receptors, Interferon; D014364:Tryptophan; D000096743:Interferon gamma Receptor; C498497:Cd207 protein, mouse; C059731:oncogene protein E7, Human papillomavirus type 16
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