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.
|Authors||Koyama, Motoko; Cheong, Melody; Markey, Kate A.; Gartlan, Kate H.; Kuns, Rachel; 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; Engwerda, C; Smyth, Mark J.; Belz, Gabrielle T.; McColl, Shaun R.; MacDonald, Kelli P. A.; Hill, Geoffrey R.|
|Journal||JOURNAL OF EXPERIMENTAL MEDICINE|