Donor colonic CD103+ dendritic cells determine the severity of acute graft-versus-host disease
Details
Publication Year 2015-07-27,Volume 212,Issue #8,Page 1303-21
Journal Title
J Exp Med
Publication Type
Journal Article
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.
Publisher
Rockefeller University Press
WEHI Research Division(s)
Molecular Immunology
PubMed ID
26169940
Terms of Use/Rights Notice
Refer to copyright notice on published article.


Creation Date: 2015-07-16 08:58:26
Last Modified: 2015-11-19 10:12:09
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