Donor colonic CD103+ dendritic cells determine the severity of acute graft-versus-host disease

Motoko Koyama, Melody Cheong, Kate A Markey, Kate H Gartlan, Rachel D Kuns, Kelly R Locke, Katie E Lineburg, Bianca E Teal, Lucie Leveque-El Mouttie, Mark D Bunting, Slavica Vuckovic, Ping Zhang, Michele W L Teng, Antiopi Varelias, Siok-Keen Tey, Leesa F Wockner, Christian R Engwerda, Mark J Smyth, Gabrielle T Belz, Shaun R McColl & 2 others Kelli P A MacDonald, Geoffrey R Hill

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

The primacy of the gastrointestinal (GI) tract in dictating the outcome of graft-versus-host disease (GVHD) is broadly accepted; however, the mechanisms controlling this effect are poorly understood. Here, we demonstrate that GVHD markedly enhances alloantigen presentation within the mesenteric lymph nodes (mLNs), mediated by donor CD103(+)CD11b(-) dendritic cells (DCs) that migrate from the colon under the influence of CCR7. Expansion and differentiation of donor T cells specifically within the mLNs is driven by profound levels of alloantigen, IL-12, and IL-6 promoted by Toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signals. Critically, alloantigen presentation in the mLNs imprints gut-homing integrin signatures on donor T cells, leading to their emigration into the GI tract where they mediate fulminant disease. These data identify a critical, anatomically distinct, donor DC subset that amplifies GVHD. We thus highlight multiple therapeutic targets and the ability of GVHD, once initiated by recipient antigen-presenting cells, to generate a profound, localized, and lethal feed-forward cascade of donor DC-mediated indirect alloantigen presentation and cytokine secretion within the GI tract.

LanguageEnglish
Pages1303-21
Number of pages19
JournalJournal of Experimental Medicine
Volume212
Issue number8
DOIs
Publication statusPublished - 27 Jul 2015
Externally publishedYes

Keywords

  • Analysis of Variance
  • Animals
  • Antigens, CD/metabolism
  • Cell Movement/immunology
  • Colon/cytology
  • Dendritic Cells/metabolism
  • Flow Cytometry
  • Graft vs Host Disease/physiopathology
  • Integrin alpha Chains/metabolism
  • Interleukin-12/metabolism
  • Interleukin-6/metabolism
  • Lymph Nodes/cytology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Receptor for Advanced Glycation End Products
  • Receptors, CCR7/metabolism
  • Receptors, Immunologic/metabolism
  • T-Lymphocytes/immunology

Cite this

Koyama, M., Cheong, M., Markey, K. A., Gartlan, K. H., Kuns, R. D., Locke, K. R., ... Hill, G. R. (2015). Donor colonic CD103+ dendritic cells determine the severity of acute graft-versus-host disease. Journal of Experimental Medicine, 212(8), 1303-21. https://doi.org/10.1084/jem.20150329
Koyama, Motoko ; Cheong, Melody ; Markey, Kate A ; Gartlan, Kate H ; Kuns, Rachel D ; Locke, Kelly R ; Lineburg, Katie E ; Teal, Bianca E ; Leveque-El Mouttie, Lucie ; Bunting, Mark D ; Vuckovic, Slavica ; Zhang, Ping ; Teng, Michele W L ; Varelias, Antiopi ; Tey, Siok-Keen ; Wockner, Leesa F ; Engwerda, Christian R ; Smyth, Mark J ; Belz, Gabrielle T ; McColl, Shaun R ; MacDonald, Kelli P A ; Hill, Geoffrey R. / Donor colonic CD103+ dendritic cells determine the severity of acute graft-versus-host disease. In: Journal of Experimental Medicine. 2015 ; Vol. 212, No. 8. pp. 1303-21.
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abstract = "The primacy of the gastrointestinal (GI) tract in dictating the outcome of graft-versus-host disease (GVHD) is broadly accepted; however, the mechanisms controlling this effect are poorly understood. Here, we demonstrate that GVHD markedly enhances alloantigen presentation within the mesenteric lymph nodes (mLNs), mediated by donor CD103(+)CD11b(-) dendritic cells (DCs) that migrate from the colon under the influence of CCR7. Expansion and differentiation of donor T cells specifically within the mLNs is driven by profound levels of alloantigen, IL-12, and IL-6 promoted by Toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signals. Critically, alloantigen presentation in the mLNs imprints gut-homing integrin signatures on donor T cells, leading to their emigration into the GI tract where they mediate fulminant disease. These data identify a critical, anatomically distinct, donor DC subset that amplifies GVHD. We thus highlight multiple therapeutic targets and the ability of GVHD, once initiated by recipient antigen-presenting cells, to generate a profound, localized, and lethal feed-forward cascade of donor DC-mediated indirect alloantigen presentation and cytokine secretion within the GI tract.",
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author = "Motoko Koyama and Melody Cheong and Markey, {Kate A} and Gartlan, {Kate H} and Kuns, {Rachel D} and Locke, {Kelly R} and Lineburg, {Katie E} and Teal, {Bianca E} and {Leveque-El Mouttie}, Lucie and Bunting, {Mark D} and Slavica Vuckovic and Ping Zhang and Teng, {Michele W L} and Antiopi Varelias and Siok-Keen Tey and Wockner, {Leesa F} and Engwerda, {Christian R} and Smyth, {Mark J} and Belz, {Gabrielle T} and McColl, {Shaun R} and MacDonald, {Kelli P A} and Hill, {Geoffrey R}",
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Koyama, M, Cheong, M, Markey, KA, Gartlan, KH, Kuns, RD, Locke, KR, Lineburg, KE, Teal, BE, Leveque-El Mouttie, L, Bunting, MD, Vuckovic, S, Zhang, P, Teng, MWL, Varelias, A, Tey, S-K, Wockner, LF, Engwerda, CR, Smyth, MJ, Belz, GT, McColl, SR, MacDonald, KPA & Hill, GR 2015, 'Donor colonic CD103+ dendritic cells determine the severity of acute graft-versus-host disease', Journal of Experimental Medicine, vol. 212, no. 8, pp. 1303-21. https://doi.org/10.1084/jem.20150329

Donor colonic CD103+ dendritic cells determine the severity of acute graft-versus-host disease. / Koyama, Motoko; Cheong, Melody; Markey, Kate A; Gartlan, Kate H; Kuns, Rachel D; Locke, Kelly R; Lineburg, Katie E; Teal, Bianca E; Leveque-El Mouttie, Lucie; Bunting, Mark D; Vuckovic, Slavica; Zhang, Ping; Teng, Michele W L; Varelias, Antiopi; Tey, Siok-Keen; Wockner, Leesa F; Engwerda, Christian R; Smyth, Mark J; Belz, Gabrielle T; McColl, Shaun R; MacDonald, Kelli P A; Hill, Geoffrey R.

In: Journal of Experimental Medicine, Vol. 212, No. 8, 27.07.2015, p. 1303-21.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Donor colonic CD103+ dendritic cells determine the severity of acute graft-versus-host disease

AU - Koyama, Motoko

AU - Cheong, Melody

AU - Markey, Kate A

AU - Gartlan, Kate H

AU - Kuns, Rachel D

AU - Locke, Kelly R

AU - Lineburg, Katie E

AU - Teal, Bianca E

AU - Leveque-El Mouttie, Lucie

AU - Bunting, Mark D

AU - Vuckovic, Slavica

AU - Zhang, Ping

AU - Teng, Michele W L

AU - Varelias, Antiopi

AU - Tey, Siok-Keen

AU - Wockner, Leesa F

AU - Engwerda, Christian R

AU - Smyth, Mark J

AU - Belz, Gabrielle T

AU - McColl, Shaun R

AU - MacDonald, Kelli P A

AU - Hill, Geoffrey R

N1 - © 2015 Koyama et al.

PY - 2015/7/27

Y1 - 2015/7/27

N2 - The primacy of the gastrointestinal (GI) tract in dictating the outcome of graft-versus-host disease (GVHD) is broadly accepted; however, the mechanisms controlling this effect are poorly understood. Here, we demonstrate that GVHD markedly enhances alloantigen presentation within the mesenteric lymph nodes (mLNs), mediated by donor CD103(+)CD11b(-) dendritic cells (DCs) that migrate from the colon under the influence of CCR7. Expansion and differentiation of donor T cells specifically within the mLNs is driven by profound levels of alloantigen, IL-12, and IL-6 promoted by Toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signals. Critically, alloantigen presentation in the mLNs imprints gut-homing integrin signatures on donor T cells, leading to their emigration into the GI tract where they mediate fulminant disease. These data identify a critical, anatomically distinct, donor DC subset that amplifies GVHD. We thus highlight multiple therapeutic targets and the ability of GVHD, once initiated by recipient antigen-presenting cells, to generate a profound, localized, and lethal feed-forward cascade of donor DC-mediated indirect alloantigen presentation and cytokine secretion within the GI tract.

AB - The primacy of the gastrointestinal (GI) tract in dictating the outcome of graft-versus-host disease (GVHD) is broadly accepted; however, the mechanisms controlling this effect are poorly understood. Here, we demonstrate that GVHD markedly enhances alloantigen presentation within the mesenteric lymph nodes (mLNs), mediated by donor CD103(+)CD11b(-) dendritic cells (DCs) that migrate from the colon under the influence of CCR7. Expansion and differentiation of donor T cells specifically within the mLNs is driven by profound levels of alloantigen, IL-12, and IL-6 promoted by Toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signals. Critically, alloantigen presentation in the mLNs imprints gut-homing integrin signatures on donor T cells, leading to their emigration into the GI tract where they mediate fulminant disease. These data identify a critical, anatomically distinct, donor DC subset that amplifies GVHD. We thus highlight multiple therapeutic targets and the ability of GVHD, once initiated by recipient antigen-presenting cells, to generate a profound, localized, and lethal feed-forward cascade of donor DC-mediated indirect alloantigen presentation and cytokine secretion within the GI tract.

KW - Analysis of Variance

KW - Animals

KW - Antigens, CD/metabolism

KW - Cell Movement/immunology

KW - Colon/cytology

KW - Dendritic Cells/metabolism

KW - Flow Cytometry

KW - Graft vs Host Disease/physiopathology

KW - Integrin alpha Chains/metabolism

KW - Interleukin-12/metabolism

KW - Interleukin-6/metabolism

KW - Lymph Nodes/cytology

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Transgenic

KW - Receptor for Advanced Glycation End Products

KW - Receptors, CCR7/metabolism

KW - Receptors, Immunologic/metabolism

KW - T-Lymphocytes/immunology

U2 - 10.1084/jem.20150329

DO - 10.1084/jem.20150329

M3 - Article

VL - 212

SP - 1303

EP - 1321

JO - Journal of Experimental Medicine

T2 - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 8

ER -