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

doi:10.1016/j.immuni.2019.08.011

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

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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 language	English (US)
Pages (from-to)	885-898.e7
Journal	Immunity
Volume	51
Issue number	5
DOIs	https://doi.org/10.1016/j.immuni.2019.08.011
State	Published - 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

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Journal Article
Research Support, N.I.H., Extramural

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2019.08.011

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Koyama, M., Mukhopadhyay, P., Schuster, I. S., Henden, A. S., Hülsdünker, J., Varelias, A., Vetizou, M., Kuns, R. D., Robb, R. J., Zhang, P., Blazar, B. R., Thomas, R., Begun, J., Waddell, N., Trinchieri, G., Zeiser, R., Clouston, A. D., Degli-Esposti, M. A., & Hill, G. R. (2019). MHC Class II Antigen Presentation by the Intestinal Epithelium Initiates Graft-versus-Host Disease and Is Influenced by the Microbiota. Immunity, 51(5), 885-898.e7. https://doi.org/10.1016/j.immuni.2019.08.011

Koyama, M, Mukhopadhyay, P, Schuster, IS, Henden, AS, Hülsdünker, J, Varelias, A, Vetizou, M, Kuns, RD, Robb, RJ, Zhang, P, Blazar, BR, Thomas, R, Begun, J, Waddell, N, Trinchieri, G, Zeiser, R, Clouston, AD, Degli-Esposti, MA & Hill, GR 2019, 'MHC Class II Antigen Presentation by the Intestinal Epithelium Initiates Graft-versus-Host Disease and Is Influenced by the Microbiota', Immunity, vol. 51, no. 5, pp. 885-898.e7. https://doi.org/10.1016/j.immuni.2019.08.011

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

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.",

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",

author = "Motoko Koyama and Pamela Mukhopadhyay and Schuster, {Iona S.} and Henden, {Andrea S.} and Jan H{\"u}lsd{\"u}nker and Antiopi Varelias and Marie Vetizou and Kuns, {Rachel D.} and Robb, {Renee J.} and Ping Zhang and Blazar, {Bruce R.} and Ranjeny Thomas and Jakob Begun and Nicola Waddell and Giorgio Trinchieri and Robert Zeiser and Clouston, {Andrew D.} and Degli-Esposti, {Mariapia A.} and Hill, {Geoffrey R.}",

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: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = nov,

day = "19",

doi = "10.1016/j.immuni.2019.08.011",

language = "English (US)",

volume = "51",

pages = "885--898.e7",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

number = "5",

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TY - JOUR

T1 - MHC Class II Antigen Presentation by the Intestinal Epithelium Initiates Graft-versus-Host Disease and Is Influenced by the Microbiota

AU - Koyama, Motoko

AU - Mukhopadhyay, Pamela

AU - Schuster, Iona S.

AU - Henden, Andrea S.

AU - Hülsdünker, Jan

AU - Varelias, Antiopi

AU - Vetizou, Marie

AU - Kuns, Rachel D.

AU - Robb, Renee J.

AU - Zhang, Ping

AU - Blazar, Bruce R.

AU - Thomas, Ranjeny

AU - Begun, Jakob

AU - Waddell, Nicola

AU - Trinchieri, Giorgio

AU - Zeiser, Robert

AU - Clouston, Andrew D.

AU - Degli-Esposti, Mariapia A.

AU - Hill, Geoffrey R.

N1 - 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.

PY - 2019/11/19

Y1 - 2019/11/19

N2 - 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.

AB - 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.

KW - MHC class II

KW - antigen presentation

KW - antigen-presenting cells

KW - dendritic cells

KW - graft-versus-host disease

KW - ileum

KW - interferon-gamma

KW - interleukin-12

KW - intestinal epithelial cells

KW - microbiome

KW - toll-like receptors

KW - type 1 innate lymphoid cells

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U2 - 10.1016/j.immuni.2019.08.011

DO - 10.1016/j.immuni.2019.08.011

M3 - Article

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AN - SCOPUS:85074847848

SN - 1074-7613

VL - 51

SP - 885-898.e7

JO - Immunity

JF - Immunity

IS - 5

ER -

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

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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