title: GVHD prevents NK-cell-dependent leukemia and virus-specific innate immunity.
abstract: Allogeneic bone marrow transplantation (allo-BMT) is a curative therapy for hematological malignancies, but is associated with significant complications, principally graft-versus-host disease (GVHD) and opportunistic infections. Natural killer (NK) cells mediate important innate immunity that provides a temporal bridge until the reconstruction of adaptive immunity. Here, we show that the development of GVHD after allo-BMT prevented NK-cell reconstitution, particularly within the maturing M1 and M2 NK-cell subsets in association with exaggerated activation, apoptosis, and autophagy. Donor T cells were critical in this process by limiting the availability of interleukin 15 (IL-15), and administration of IL-15/IL-15Rα or immune suppression with rapamycin could restore NK-cell reconstitution. Importantly, the NK-cell defect induced by GVHD resulted in the failure of NK-cell-dependent in vivo cytotoxicity and graft-versus-leukemia effects. Control of cytomegalovirus infection after allo-BMT was also impaired during GVHD. Thus, during GVHD, donor T cells compete with NK cells for IL-15 thereby inducing profound defects in NK-cell reconstitution that compromise both leukemia and pathogen-specific immunity.
authors.affiliation: Bone Marrow Transplantation Laboratory, Immunology Department, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Bunting
authors.affiliation: Bone Marrow Transplantation Laboratory, Immunology Department, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, QLD, Australia.|School of Medicine, University of Queensland, Brisbane, QLD, Australia.
authors.forename: Antiopi
authors.initials: A
authors.lastname: Varelias
authors.affiliation: Immunology in Cancer and Infection Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.|Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Department of Medical Biology and.|Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Fernando
authors.initials: F
authors.lastname: Souza-Fonseca-Guimaraes
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia.|Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA, Australia.
authors.forename: Iona S
authors.initials: IS
authors.lastname: Schuster
authors.affiliation: Antigen Presentation and Immunoregulation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Katie E
authors.initials: KE
authors.lastname: Lineburg
authors.affiliation: Bone Marrow Transplantation Laboratory, Immunology Department, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Kuns
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia.|Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Fleming
authors.affiliation: Bone Marrow Transplantation Laboratory, Immunology Department, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Locke
authors.affiliation: Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Department of Medical Biology and.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Huntington
authors.affiliation: Masonic Cancer Center and.|Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: School of Medicine, University of Queensland, Brisbane, QLD, Australia.|Gordon and Jessie Gilmour Leukemia Research Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; and.|The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Lane
authors.affiliation: Bone Marrow Transplantation Laboratory, Immunology Department, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, QLD, Australia.|School of Medicine, University of Queensland, Brisbane, QLD, Australia.|The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Siok-Keen
authors.initials: SK
authors.lastname: Tey
authors.affiliation: Antigen Presentation and Immunoregulation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Kelli P A
authors.initials: KP
authors.lastname: MacDonald
authors.affiliation: School of Medicine, University of Queensland, Brisbane, QLD, Australia.|Immunology in Cancer and Infection Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia.|Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA, Australia.
authors.forename: Mariapia A
authors.initials: MA
authors.lastname: Degli-Esposti
authors.affiliation: Bone Marrow Transplantation Laboratory, Immunology Department, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, QLD, Australia.|School of Medicine, University of Queensland, Brisbane, QLD, Australia.|The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
mesh_terms: D000818:Animals; D001343:Autophagy; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000276:immunology* / Q000302:isolation & purification; D003586:Cytomegalovirus Infections / Q000150:complications / Q000276:immunology* / Q000473:pathology; D005260:Female; D006086:Graft vs Host Disease / Q000150:complications / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate; D019409:Interleukin-15 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology*; D007938:Leukemia / Q000150:complications / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014184:Transplantation, Homologous / Q000009:adverse effects
chemical_list: D019409:Interleukin-15