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

J Exp Med. 2015 Jul 27;212(8):1303-21. doi: 10.1084/jem.20150329. Epub 2015 Jul 13.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Lymph Nodes / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Receptor for Advanced Glycation End Products
  • Receptors, CCR7 / metabolism
  • Receptors, Immunologic / metabolism
  • T-Lymphocytes / immunology


  • Antigens, CD
  • CCR7 protein, human
  • Integrin alpha Chains
  • Interleukin-6
  • Receptor for Advanced Glycation End Products
  • Receptors, CCR7
  • Receptors, Immunologic
  • alpha E integrins
  • Interleukin-12