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

Motoko Koyama, Pamela Mukhopadhyay, Iona S. Schuster, Andrea S. Henden, Jan Hülsdünker, Antiopi Varelias, Marie Vetizou, Rachel D. Kuns, Renee J. Robb, Ping Zhang, Bruce R. Blazar, Ranjeny Thomas, Jakob Begun, Nicola Waddell, Giorgio Trinchieri, Robert Zeiser, Andrew D. Clouston, Mariapia A. Degli-Esposti, Geoffrey R. Hill

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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. Graft-versus-host disease in the gastrointestinal tract is the principal determinant of lethality following allogeneic bone marrow transplantation. Koyama et al. find that MHC class II-dependent antigen presentation by ileal intestinal epithelial cells (IECs) is critical for the initiation of lethal GVHD in the gut, define the requirements for IEC MHC class II expression, and propose IL-12 neutralization as a therapeutic strategy for GVHD.

Original languageEnglish (US)
Pages (from-to)885-898.e7
JournalImmunity
Volume51
Issue number5
DOIs
StatePublished - Nov 19 2019

Bibliographical note

Funding Information:
From QIMR Berghofer, we thank C. Winterford for expert preparation of histology samples; M. Rist, P. Hall, and G. Chojnowski for expert cell sorting; M. Flynn for expert generation of the graphics; and the animal facility for attentive animal care. We thank S. Robine (Institut Curie-CNRS, France) and R.S. Blumberg (Harvard Medical School, USA) for the VillinCre-ERT2 mice. This work was supported by research grants from the National Health and Medical Research Council (NHMRC), Australia (APP1086685) and the National Heart, Lung, and Blood Institute of the NIH (R01HL148164), United States. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. M.K. was a Leukaemia Foundation of Australia fellow. N.W. is a NHMRC senior research fellow. M.A.D.-E. is a NHMRC principal research fellow. G.R.H. was a NHMRC senior principal research fellow. R.Z. is a fellow of Deutsche Krebshilfe (111639), Germany. B.R.B. is supported in part by the NIH (R37 AI34495). M.K. designed, performed, and analyzed most experiments and wrote the paper. P.M. performed the bioinformatics analysis. I.S.S. A.V. and P.Z. helped design experiments. I.S.S. A.S.H. J.H. M.V. R.D.K. and R.J.R. performed research. J.H. and A.D.C. performed the histological analysis. B.R.B. R.T. J.B. N.W. G.T. R.Z. and A.D.C. provided data interpretation. M.A.D.-E. helped design experiments and wrote the paper. G.R.H. designed experiments and wrote the paper. Results were discussed and the manuscript was critically commented on and edited by all authors. The authors declare no competing interests.

Funding Information:
From QIMR Berghofer, we thank C. Winterford for expert preparation of histology samples; M. Rist, P. Hall, and G. Chojnowski for expert cell sorting; M. Flynn for expert generation of the graphics; and the animal facility for attentive animal care. We thank S. Robine (Institut Curie-CNRS, France) and R.S. Blumberg (Harvard Medical School, USA) for the Villin Cre-ER T2 mice. This work was supported by research grants from the National Health and Medical Research Council (NHMRC), Australia ( APP1086685 ) and the National Heart, Lung, and Blood Institute of the NIH ( R01HL148164 ), United States. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. M.K. was a Leukaemia Foundation of Australia fellow. N.W. is a NHMRC senior research fellow. M.A.D.-E. is a NHMRC principal research fellow. G.R.H. was a NHMRC senior principal research fellow. R.Z. is a fellow of Deutsche Krebshilfe ( 111639 ), Germany. B.R.B. is supported in part by the NIH ( R37 AI34495 ).

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

  • MHC class II
  • antigen presentation
  • antigen-presenting cells
  • dendritic cells
  • graft-versus-host disease
  • ileum
  • interferon-gamma
  • interleukin-12
  • intestinal epithelial cells
  • microbiome
  • toll-like receptors
  • type 1 innate lymphoid cells

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