title: Corruption of dendritic cell antigen presentation during acute GVHD leads to regulatory T-cell failure and chronic GVHD.
abstract: Chronic graft-versus-host disease (cGVHD) is a major cause of late mortality following allogeneic bone marrow transplantation (BMT) and is characterized by tissue fibrosis manifesting as scleroderma and bronchiolitis obliterans. The development of acute GVHD (aGVHD) is a powerful clinical predictor of subsequent cGVHD, suggesting that aGVHD may invoke the immunologic pathways responsible for cGVHD. In preclinical models in which sclerodermatous cGVHD develops after a preceding period of mild aGVHD, we show that antigen presentation within major histocompatibility complex (MHC) class II of donor dendritic cells (DCs) is markedly impaired early after BMT. This is associated with a failure of regulatory T-cell (Treg) homeostasis and cGVHD. Donor DC-restricted deletion of MHC class II phenocopied this Treg deficiency and cGVHD. Moreover, specific depletion of donor Tregs after BMT also induced cGVHD, whereas adoptive transfer of Tregs ameliorated it. These data demonstrate that the defect in Treg homeostasis seen in cGVHD is a causative lesion and is downstream of defective antigen presentation within MHC class II that is induced by aGVHD.
authors.affiliation: Antigen Presentation and Immunoregulation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia; The University of Queensland, Brisbane, Australia;
authors.forename: Lucie
authors.identifier: 0000-0003-0744-6067
authors.initials: L
authors.lastname: Leveque-El Mouttie
authors.affiliation: Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia;
authors.forename: Motoko
authors.initials: M
authors.lastname: Koyama
authors.affiliation: Antigen Presentation and Immunoregulation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia;
authors.forename: Laetitia
authors.initials: L
authors.lastname: Le Texier
authors.affiliation: The University of Queensland, Brisbane, Australia; Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia; Department of Haematology, Royal Brisbane and Women's Hospital, Brisbane, Australia;
authors.forename: Kate A
authors.identifier: 0000-0002-7064-2362
authors.initials: KA
authors.lastname: Markey
authors.affiliation: Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia; School of Biomolecular and Physical Sciences, Griffith University, Nathan, Australia;
authors.forename: Melody
authors.initials: M
authors.lastname: Cheong
authors.affiliation: Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia;
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Kuns
authors.affiliation: Antigen Presentation and Immunoregulation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia;
authors.forename: Katie E
authors.identifier: 0000-0002-5712-2610
authors.initials: KE
authors.lastname: Lineburg
authors.affiliation: Antigen Presentation and Immunoregulation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia;
authors.forename: Bianca E
authors.initials: BE
authors.lastname: Teal
authors.affiliation: Antigen Presentation and Immunoregulation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia;
authors.forename: Kylie A
authors.initials: KA
authors.lastname: Alexander
authors.affiliation: Envoi Pathology, Brisbane, Australia; and.
authors.forename: Andrew D
authors.identifier: 0000-0002-9601-7952
authors.initials: AD
authors.lastname: Clouston
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, University of Minnesota, Minneapolis, MN.
authors.forename: Bruce R
authors.identifier: 0000-0002-9608-9841
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia; Department of Haematology, Royal Brisbane and Women's Hospital, Brisbane, Australia;
authors.forename: Geoffrey R
authors.identifier: 0000-0001-8864-6495
authors.initials: GR
authors.lastname: Hill
authors.affiliation: Antigen Presentation and Immunoregulation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia;
authors.forename: Kelli P A
authors.initials: KP
authors.lastname: MacDonald
mesh_terms: D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D002908:Chronic Disease; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology*; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology* / Q000637:transplantation
chemical_list: D000949:Histocompatibility Antigens Class II