title: Acute graft-versus-host disease is regulated by an IL-17-sensitive microbiome.
abstract: Donor T-cell-derived interleukin-17A (IL-17A) can mediate late immunopathology in graft-versus-host disease (GVHD), however protective roles remain unclear. Using multiple cytokine and cytokine receptor subunit knockout mice, we demonstrate that stem cell transplant recipients lacking the ability to generate or signal IL-17 develop intestinal hyper-acute GVHD. This protective effect is restricted to the molecular interaction of IL-17A and/or IL-17F with the IL-17 receptor A/C (IL-17RA/C). The protection from GVHD afforded by IL-17A required secretion from, and signaling in, both hematopoietic and nonhematopoietic host tissue. Given the intestinal-specificity of the disease in these animals, we cohoused wild-type (WT) with IL-17RA and IL-17RC-deficient mice, which dramatically enhanced the susceptibility of WT mice to acute GVHD. Furthermore, the gut microbiome of WT mice shifted toward that of the IL-17RA/C mice during cohousing prior to transplant, confirming that an IL-17-sensitive gut microbiota controls susceptibility to acute GVHD. Finally, induced IL-17A depletion peritransplant also enhanced acute GVHD, consistent with an additional protective role for this cytokine independent of effects on dysbiosis.
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.|School of Medicine and.
authors.forename: Antiopi
authors.initials: A
authors.lastname: Varelias
authors.affiliation: Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, The University of Queensland, QLD, Australia.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Ormerod
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Bunting
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.|School of Medicine and.
authors.forename: Motoko
authors.initials: M
authors.lastname: Koyama
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.|School of Medicine and.
authors.forename: Kate H
authors.initials: KH
authors.lastname: Gartlan
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Kuns
authors.affiliation: Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, The University of Queensland, QLD, Australia.
authors.forename: Nancy
authors.initials: N
authors.lastname: Lachner
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Locke
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Chun Y
authors.initials: CY
authors.lastname: Lim
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Henden
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Envoi Specialist Pathologists, Brisbane, QLD, Australia.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Clouston
authors.affiliation: Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
authors.forename: Sumaira Z
authors.initials: SZ
authors.lastname: Hasnain
authors.affiliation: Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McGuckin
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, University of Minnesota, Minneapolis, MN; and.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Kelli P A
authors.initials: KP
authors.lastname: MacDonald
authors.affiliation: Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, The University of Queensland, QLD, Australia.
authors.forename: Philip
authors.initials: P
authors.lastname: Hugenholtz
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.|School of Medicine and.|Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
mesh_terms: D000208:Acute Disease; D000818:Animals; D004195:Disease Models, Animal; D064806:Dysbiosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000069196:Gastrointestinal Microbiome / Q000276:immunology*; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D007410:Intestinal Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017710:Lymphocyte Transfusion; D051379:Mice; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000276:immunology
chemical_list: C098680:Il17a protein, mouse; C491673:Il17ra protein, mouse; C508527:Il17rc protein, mouse; D020381:Interleukin-17; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17