Recipient nonhematopoietic antigen-presenting cells are sufficient to induce lethal acute graft-versus-host disease

Abstract

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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Figure 1: aGVHD is initiated by MHC class II antigen presentation within host APCs.
Figure 2: Antigen presentation within MHC class-II on host APCs induces profound donor T cell expansion, primarily within the gastrointestinal (GI) tract.
Figure 3: Host dendritic cells are not required to induce aGVHD.
Figure 4: Recipient DC depletion amplifies aGVHD directed to MHC.
Figure 5: Recipient nonhematopoietic APCs are sufficient to induce lethal aGVHD.
Figure 6: Nonhematopoietic APCs in gastrointestinal tract induce GVHD.

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Acknowledgements

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.

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M.K. designed and performed research and helped write the paper, R.D.K., S.D.O., N.C.R., Y.A.W., A.L.J.D., K.E.L., M.C., R.J.R., K.A.M. and A.V. performed research, B.M. and G.J.H. provided essential transgenic mice, A.D.C. performed blinded histological assessment, C.R.E. provided reagents and data interpretation, P.B. performed confocal microscopy and data interpretation and K.P.A.M. and G.R.H. provided experimental design and wrote the paper.

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Correspondence to Geoffrey R Hill.

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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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