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MHC Class II Antigen Presentation by the Intestinal Epithelium Initiates Graft-versus-Host Disease and Is Influenced by the Microbiota.

Authors
  • Koyama, Motoko1
  • Mukhopadhyay, Pamela2
  • Schuster, Iona S3
  • Henden, Andrea S4
  • Hülsdünker, Jan5
  • Varelias, Antiopi6
  • Vetizou, Marie7
  • Kuns, Rachel D6
  • Robb, Renee J6
  • Zhang, Ping6
  • Blazar, Bruce R8
  • Thomas, Ranjeny9
  • Begun, Jakob10
  • Waddell, Nicola2
  • Trinchieri, Giorgio7
  • Zeiser, Robert11
  • Clouston, Andrew D12
  • Degli-Esposti, Mariapia A3
  • Hill, Geoffrey R13
  • 1 Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Electronic address: [email protected] , (Australia)
  • 2 Medical Genomics Laboratory, Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia. , (Australia)
  • 3 Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA 6009, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia; Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. , (Australia)
  • 4 Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia. , (Australia)
  • 5 Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert Ludwigs University Freiburg, Freiburg 79106, Germany; Spemann Graduate School of Biology and Medicine, University Freiburg, Freiburg 79085, Germany; Faculty of Biology, University Freiburg, Freiburg 79104, Germany. , (Germany)
  • 6 Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia. , (Australia)
  • 7 Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
  • 8 Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
  • 9 Diamantina Institute, Translational Research Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia. , (Australia)
  • 10 Mater Research Institute, University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia. , (Australia)
  • 11 Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Albert Ludwigs University Freiburg, Freiburg 79106, Germany. , (Germany)
  • 12 Envoi Specialist Pathologists, Brisbane, QLD 4006, Australia. , (Australia)
  • 13 Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Division of Medical Oncology, University of Washington, Seattle, WA 98109, USA. Electronic address: [email protected] , (Australia)
Type
Published Article
Journal
Immunity
Publication Date
Nov 19, 2019
Volume
51
Issue
5
Identifiers
DOI: 10.1016/j.immuni.2019.08.011
PMID: 31542340
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract is the principal determinant of lethality following allogeneic bone marrow transplantation (BMT). Here, we examined the mechanisms that initiate GVHD, including the relevant antigen-presenting cells. MHC class II was expressed on intestinal epithelial cells (IECs) within the ileum at steady state but was absent from the IECs of germ-free mice. IEC-specific deletion of MHC class II prevented the initiation of lethal GVHD in the GI tract. MHC class II expression on IECs was absent from mice deficient in the TLR adaptors MyD88 and TRIF and required IFNγ secretion by lamina propria lymphocytes. IFNγ responses are characteristically driven by IL-12 secretion from myeloid cells. Antibiotic-mediated depletion of the microbiota inhibited IL-12/23p40 production by ileal macrophages. IL-12/23p40 neutralization prevented MHC class II upregulation on IECs and initiation of lethal GVHD in the GI tract. Thus, MHC class II expression by IECs in the ileum initiates lethal GVHD, and blockade of IL-12/23p40 may represent a readily translatable therapeutic strategy. Copyright © 2019 Elsevier Inc. All rights reserved.

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