The presentation pathways by which allogeneic peptides induce graft-versus-host disease (GVHD) are unclear. We developed a bone marrow transplant (BMT) system in mice whereby presentation of a processed recipient peptide within major histocompatibility complex (MHC) class II molecules could be spatially and temporally quantified. Whereas donor antigen presenting cells (APCs) could induce lethal acute GVHD via MHC class II, recipient APCs were 100–1,000 times more potent in this regard. After myeloablative irradiation, T cell activation and memory differentiation occurred in lymphoid organs independently of alloantigen. Unexpectedly, professional hematopoietic-derived recipient APCs within lymphoid organs had only a limited capacity to induce GVHD, and dendritic cells were not required. In contrast, nonhematopoietic recipient APCs within target organs induced universal GVHD mortality and promoted marked alloreactive donor T cell expansion within the gastrointestinal tract and inflammatory cytokine generation. These data challenge current paradigms, suggesting that experimental lethal acute GVHD can be induced by nonhematopoietic recipient APCs.
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Supported by research grants from the Australian National Health and Medical Research Council (NHMRC). G.R.H. is an NHMRC Australia Fellow. C.R.E. is an NHMRC Research Fellow. K.P.A.M. is a Cancer Council of Queensland Fellow. K.A.M. is an NHMRC Clinical Training Fellow. We thank C. Winterford for expert preparation of histology samples and P. Hall and G. Chojnowski for expert cell sorting. We obtained transgenic and knockout mice as follows: OT-II, R. Steptoe, Diamantina Institute; H2dlAb1-Ea, Australian National University; β-actin-luciferase25, R. Negrin, Stanford University; TEa14, J. Bromberg, Albert Einstein College; cfms.EGFP12, D. Hume, Institute of Molecular Biology; MHC class II.EGFP, B. Fazekas de St Groth, Garvan Institute.
The authors declare no competing financial interests.
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Koyama, M., Kuns, R., Olver, S. et al. Recipient nonhematopoietic antigen-presenting cells are sufficient to induce lethal acute graft-versus-host disease. Nat Med 18, 135–142 (2012). https://doi.org/10.1038/nm.2597
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