title: Donor colonic CD103+ dendritic cells determine the severity of acute graft-versus-host disease.
abstract: The primacy of the gastrointestinal (GI) tract in dictating the outcome of graft-versus-host disease (GVHD) is broadly accepted; however, the mechanisms controlling this effect are poorly understood. Here, we demonstrate that GVHD markedly enhances alloantigen presentation within the mesenteric lymph nodes (mLNs), mediated by donor CD103(+)CD11b(-) dendritic cells (DCs) that migrate from the colon under the influence of CCR7. Expansion and differentiation of donor T cells specifically within the mLNs is driven by profound levels of alloantigen, IL-12, and IL-6 promoted by Toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signals. Critically, alloantigen presentation in the mLNs imprints gut-homing integrin signatures on donor T cells, leading to their emigration into the GI tract where they mediate fulminant disease. These data identify a critical, anatomically distinct, donor DC subset that amplifies GVHD. We thus highlight multiple therapeutic targets and the ability of GVHD, once initiated by recipient antigen-presenting cells, to generate a profound, localized, and lethal feed-forward cascade of donor DC-mediated indirect alloantigen presentation and cytokine secretion within the GI tract.
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia Motoko.Koyama@qimrberghofer.edu.au Geoff.Hill@qimrberghofer.edu.au.
authors.forename: Motoko
authors.initials: M
authors.lastname: Koyama
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Melody
authors.initials: M
authors.lastname: Cheong
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Kate A
authors.initials: KA
authors.lastname: Markey
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Kate H
authors.initials: KH
authors.lastname: Gartlan
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Kuns
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Locke
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Katie E
authors.initials: KE
authors.lastname: Lineburg
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Bianca E
authors.initials: BE
authors.lastname: Teal
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Lucie
authors.initials: L
authors.lastname: Leveque-El Mouttie
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Bunting
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Slavica
authors.initials: S
authors.lastname: Vuckovic
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Michele W L
authors.initials: MW
authors.lastname: Teng
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Antiopi
authors.initials: A
authors.lastname: Varelias
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia The Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia.
authors.forename: Siok-Keen
authors.initials: SK
authors.lastname: Tey
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Leesa F
authors.initials: LF
authors.lastname: Wockner
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Engwerda
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
authors.affiliation: The University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Shaun R
authors.initials: SR
authors.lastname: McColl
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Kelli P A
authors.initials: KP
authors.lastname: MacDonald
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia The Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia Motoko.Koyama@qimrberghofer.edu.au Geoff.Hill@qimrberghofer.edu.au.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002465:Cell Movement / Q000276:immunology*; D003106:Colon / Q000166:cytology*; D003713:Dendritic Cells / Q000378:metabolism*; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000503:physiopathology*; D039001:Integrin alpha Chains / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D000067759:Receptor for Advanced Glycation End Products; D054400:Receptors, CCR7 / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D015703:Antigens, CD; C515370:CCR7 protein, human; D039001:Integrin alpha Chains; D015850:Interleukin-6; D000067759:Receptor for Advanced Glycation End Products; D054400:Receptors, CCR7; D011971:Receptors, Immunologic; C091367:alpha E integrins; D018664:Interleukin-12