title: Tc17 cells are a proinflammatory, plastic lineage of pathogenic CD8+ T cells that induce GVHD without antileukemic effects.
abstract: IL-17-producing cells are important mediators of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Here we demonstrate that a distinct CD8(+) Tc17 population develops rapidly after SCT but fails to maintain lineage fidelity such that they are unrecognizable in the absence of a fate reporter. Tc17 differentiation is dependent on alloantigen presentation by host dendritic cells (DCs) together with IL-6. Tc17 cells express high levels of multiple prototypic lineage-defining transcription factors (eg, RORγt, T-bet) and cytokines (eg, IL-17A, IL-22, interferon-γ, granulocyte macrophage colony-stimulating factor, IL-13). Targeted depletion of Tc17 early after transplant protects from lethal acute GVHD; however, Tc17 cells are noncytolytic and fail to mediate graft-versus-leukemia (GVL) effects. Thus, the Tc17 differentiation program during GVHD culminates in a highly plastic, hyperinflammatory, poorly cytolytic effector population, which we term "inflammatory iTc17" (iTc17). Because iTc17 cells mediate GVHD without contributing to GVL, therapeutic inhibition of iTc17 development in a clinical setting represents an attractive approach for separating GVHD and GVL.
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; School of Medicine, University of Queensland, Herston, QLD, Australia;
authors.forename: Kate H
authors.initials: KH
authors.lastname: Gartlan
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors.forename: Kate A
authors.initials: KA
authors.lastname: Markey
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; School of Medicine, University of Queensland, Herston, QLD, Australia;
authors.forename: Antiopi
authors.initials: A
authors.lastname: Varelias
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors.forename: Mark D
authors.initials: MD
authors.lastname: Bunting
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors.forename: Motoko
authors.initials: M
authors.lastname: Koyama
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Kuns
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors.forename: Neil C
authors.initials: NC
authors.lastname: Raffelt
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Olver
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors.forename: Katie E
authors.initials: KE
authors.lastname: Lineburg
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors.forename: Melody
authors.initials: M
authors.lastname: Cheong
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors.forename: Bianca E
authors.initials: BE
authors.lastname: Teal
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors.forename: Mary
authors.initials: M
authors.lastname: Lor
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide and Centre for Molecular Pathology, Adelaide, SA, Australia;
authors.forename: Iain
authors.initials: I
authors.lastname: Comerford
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors.forename: Michele W L
authors.initials: MW
authors.lastname: Teng
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; School of Medicine, University of Queensland, Herston, QLD, Australia;
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, Australia;
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.affiliation: Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC, Australia; Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff, United Kingdom;
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.affiliation: Division of Molecular Immunology, MRC National Institute for Medical Research, Mill Hill, London, United Kingdom;
authors.forename: Brigitta
authors.initials: B
authors.lastname: Stockinger
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors.forename: Glen M
authors.initials: GM
authors.lastname: Boyle
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors.forename: Steven W
authors.initials: SW
authors.lastname: Lane
authors.affiliation: Envoi Specialist Pathologists, Brisbane, QLD, Australia; and.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Clouston
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide and Centre for Molecular Pathology, Adelaide, SA, Australia;
authors.forename: Shaun R
authors.initials: SR
authors.lastname: McColl
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;
authors.forename: Kelli P A
authors.initials: KP
authors.lastname: MacDonald
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology*; D020544:Graft vs Leukemia Effect; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D033581:Stem Cell Transplantation / Q000009:adverse effects*; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology*
chemical_list: D016827:CD8 Antigens; D020381:Interleukin-17