title: NK cells require IL-28R for optimal in vivo activity.
abstract: Natural killer (NK) cells are naturally circulating innate lymphoid cells that protect against tumor initiation and metastasis and contribute to immunopathology during inflammation. The signals that prime NK cells are not completely understood, and, although the importance of IFN type I is well recognized, the role of type III IFN is comparatively very poorly studied. IL-28R-deficient mice were resistant to LPS and cecal ligation puncture-induced septic shock, and hallmark cytokines in these disease models were dysregulated in the absence of IL-28R. IL-28R-deficient mice were more sensitive to experimental tumor metastasis and carcinogen-induced tumor formation than WT mice, and additional blockade of interferon alpha/beta receptor 1 (IFNAR1), but not IFN-γ, further enhanced metastasis and tumor development. IL-28R-deficient mice were also more susceptible to growth of the NK cell-sensitive lymphoma, RMAs. Specific loss of IL-28R in NK cells transferred into lymphocyte-deficient mice resulted in reduced LPS-induced IFN-γ levels and enhanced tumor metastasis. Therefore, by using IL-28R-deficient mice, which are unable to signal type III IFN-λ, we demonstrate for the first time, to our knowledge, the ability of IFN-λ to directly regulate NK cell effector functions in vivo, alone and in the context of IFN-αβ.
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Medicine, University of Queensland, St. Lucia, QLD 4006, Australia;
authors.forename: Fernando
authors.initials: F
authors.lastname: Souza-Fonseca-Guimaraes
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Medicine, University of Queensland, St. Lucia, QLD 4006, Australia;
authors.forename: Arabella
authors.initials: A
authors.lastname: Young
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia;
authors.forename: Deepak
authors.initials: D
authors.lastname: Mittal
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia;
authors.forename: Ludovic
authors.initials: L
authors.lastname: Martinet
authors.affiliation: Translational Leukaemia Research Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia;
authors.forename: Claudia
authors.initials: C
authors.lastname: Bruedigam
authors.affiliation: Division of Cell Biology, Biomedical Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan;
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, University of Western Australia, Crawley, WA 6009, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia;
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Andoniou
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, University of Western Australia, Crawley, WA 6009, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia;
authors.forename: Mariapia A
authors.initials: MA
authors.lastname: Degli-Esposti
authors.affiliation: Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; and Department of Bone Marrow Transplantation, Royal Brisbane Hospital, Brisbane, QLD 4006, Australia.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Medicine, University of Queensland, St. Lucia, QLD 4006, Australia; mark.smyth@qimrberghofer.edu.au.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000818:Animals; D002273:Carcinogens; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D004731:Endotoxins / Q000378:metabolism; D005434:Flow Cytometry; D017353:Gene Deletion; D005786:Gene Expression Regulation; D007370:Interferon Type I / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000166:cytology*; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D012333:RNA, Messenger / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism*; D012772:Shock, Septic / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002273:Carcinogens; D016207:Cytokines; D004731:Endotoxins; D007370:Interferon Type I; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D018121:Receptors, Cytokine; C471046:interleukin 28alpha receptor
keywords: IL-28R; LPS; NK cells; anti-tumor; interferon