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

The Queensland Institute of Medical Research, Brisbane, Australia.
Nature medicine (Impact Factor: 27.36). 11/2011; 18(1):135-42. DOI: 10.1038/nm.2597
Source: PubMed


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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Available from: Yana Wilson, Oct 14, 2015
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    • "Lymph node stromal cells express surface MHC-II MHC-II expression was traditionally thought to be restricted to hematopoietic-derived professional antigen-presenting cells, such as dendritic cells, macrophages, and B cells. It is now clear, however, that cells of other origins are also able to express MHC-II molecules and to present antigens to CD4 + T cells (Stagg et al., 2006; Kreisel et al., 2010; Koyama et al., 2012). Amongst these other cells, lymph node stromal cells express MHC-II in the steady-state (Figure 1 and (Malhotra et al., 2012; Dubrot et al., 2014)). "
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    • "Moreover, when all other hematopoietic APCs are absent, DCs alone may induce GVHD (5, 105). However, recent reports indicate that host-derived hematopoietic APCs are dispensable for inducing GVHD, specifically CD11c+DCs and/or pDCs depletion in the presence of other APCs (106, 107) does not attenuate GVHD, it might even increase lethal GVHD (15, 107). These data clearly demonstrate that host DCs are therefore not crucial for the induction of GVHD and could even play a regulatory role. "
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    ABSTRACT: Dendritic cells (DCs) are the most potent antigen presenting cells. DCs play a pivotal role in determining the character and magnitude of immune responses to tumors. Host and donor hematopoietic-derived DCs play a critical role in the development of graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation. GVHD is tightly linked with the graft-versus-tumor (GVT) effect. Although both host and donor DCs are important regulators of GVHD, the role of DCs in GVT is poorly understood. GVT is caused by donor T cells that attack recipient tumor cells. The donor T cells recognize alloantigens, and tumor specific antigens (TSAs) are mediating GVHD. The process of presentation of these antigens, especially TSAs remains unknown. Recent data suggested that DC may be essential role for inducing GVT. The mechanisms that DCs possess may include direct presentation, cross-presentation, cross-dressing. The role they play in GVT will be reviewed.
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    • "aGVHD is caused by donor T cell-mediated recognition in response to recipient nonhematopoietic antigen presenting cells, especially dendritic cells. In consequence, in the immune reaction, alloantigens are presented to alloreactive T cells with huge amounts of cytokines [3, 4]. Unlike aGVHD, cGVHD is generated by thymic damage, production of aberrant B cells, defective function of T cells, along with cytokine dysregulation [5]. "
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