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 McCollKelli P A MacDonald, Geoffrey R Hill

Research output: Contribution to journalArticle

50 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.

Original languageEnglish
Pages (from-to)1303-21
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