Donor CD103+ dendritic cells in the colon engender lethal graft-versus-host disease (TRAN1P.938)
| Autor: | Motoko Koyama, Melody Cheong, Kate Markey, Kate Gartlan, Rachel Kuns, Kelly Locke, Katie Lineburg, Bianca Teal, Mark Bunting, Slavica Vuckovic, Ping Zhang, Michele Teng, Antiopi Varelias, Siok-Keen Tey, Leesa Wockner, Christian Engwerda, Mark Smyth, Gabrielle Belz, Shaun McColl, Kelli MacDonald, Geoffrey Hill |
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| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 194:140.20-140.20 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | The spatial and temporal nature of donor antigen presentation during graft-versus-host disease (GVHD) and its relevance to disease severity are poorly understood. Here we use luciferase expressing TCR transgenic CD4+ T cells specific for indirect alloantigen presentation within MHC class II to demonstrate that GVHD markedly enhances indirect presentation within the mesenteric lymph nodes (mLN). By using antibody specific for alloantigen complexed with donor MHC and IRF4 and CCR7 deficient donors we demonstrate that this presentation is entirely mediated by the donor CD103+CD11bneg dendritic cell (DC) subset that migrates from the colon under the influence of CCR7. We used IL-12, IL-6, MyD88/TRIF and receptor for advanced glycation end products (RAGE) deficient grafts to demonstrate that this differentiation of donor T cells in the mLN during GVHD is driven by high levels of alloantigen and local IL-12 and IL-6 secretion elicited by Toll-like receptor and RAGE signals. Notably, alloantigen presentation by CD103+ DC migrating from the colon imprints gut-homing integrin signatures on donor T cells in the mLN, leading to their emigration into the gastrointestinal (GI) tract where they mediate fulminant GVHD. These data highlight multiple therapeutic targets and the ability of GVHD, once initiated by recipient APC, to generate a profound and localized feed-forward cascade of indirect antigen presentation and cytokine secretion within the GI tract, culminating in lethality. |
| Databáze: | OpenAIRE |
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