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

Graft-versus-host disease (GVHD) can be a life-threatening complication of bone marrow transplantation (BMT). Understanding the mechanisms causing GVHD is important to developing treatments or preventive therapies. In this issue, Koyama et al . report the surprising finding that recipient nonhematopoietic antigen-presenting cells, rather than dendritic cells, are the crucial factor in inducing CD4 + T cell–dependent GVHD and death in mice. 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.