Donor colonic CD103+ dendritic cells determine the severity of acute graft-versus-host disease
- 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, MW; Varelias, A; Tey, SK; Wockner, LF; Engwerda, CR; Smyth, MJ; Belz, GT; McColl, SR; MacDonald, KP; Hill, GR;
Publication Year 2015-07-27, Volume 212, Issue #8, Page 1303-21
- Journal Title
- J Exp Med
- Publication Type
- Journal Article
- 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.
- Rockefeller University Press
- WEHI Research Division(s)
- Molecular Immunology
- PubMed ID
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2015-07-16 08:58:26Last Modified: 2015-11-19 10:12:09