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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Although the effects of type II-IFN (IFN-␥) on GVHD and leukemia relapse are well studied, the effects of type I-interferon (type I-IFN, IFN-␣/␤) remain unclear. We investigated this using type I-IFN receptordeficient mice and exogenous IFN-␣ administration in established models of GVHD and GVL. Type I-IFN signaling in host tissue prevented severe colontargeted GVHD in CD4-dependent models of GVHD directed toward either major histocompatibility antigens or multiple minor histocompatibility antigens. This protection was the result of suppression of donor CD4 ؉ T-cell proliferation and differentiation. Studies in chimeric recipients demonstrated this was due to type I-IFN signaling in hematopoietic tissue. Consistent with this finding, administration of IFN-␣ during conditioning inhibited donor CD4 ؉ proliferation and differentiation. In contrast, CD8-dependent GVHD and GVL effects were enhanced when type I-IFN signaling was intact in the host or donor, respectively. This finding reflected the ability of type I-IFN to both sensitize host target tissue/leukemia to cell-mediated cytotoxicity and augment donor CTL function. These data confirm that type I-IFN plays an important role in defining the balance of GVHD and GVL responses and suggests that administration of the cytokine after BM transplantation could be studied prospectively in patients at high risk of relapse. (Blood. 2011;118(12):3399-3409) IntroductionAlthough allogeneic BM transplantation is curative therapy for a majority of hematologic malignancies, its application has been limited by the development of GVHD. GVHD is the result of immunologic damage to the host tissue by alloreactive T cells from the incoming donor graft. Unfortunately, the development of detrimental GVHD is closely intertwined with therapeutic GVL responses. GVL responses are important for eradication of residual host malignancy and are primarily mediated by alloreactive donor T and natural killer (NK) cells. Therapeutic approaches to separate these phenomena are urgently needed.The IFNs were first discovered as a result of their capacity to confer cell resistance to viral infection. 1 There are 2 distinct IFN types, type I and type II, and although both groups induce antiviral defense mechanisms in cells, primarily by limiting replication, they exhibit distinct immunologic properties. After allograft rejection, it is well established that the type II-IFN, IFN-␥, is a dominant Th1 cytokine, exerting pleotropic effects on both hematopoietic and nonhematopoietic cells. Importantly, IFN-␥ has differential effects on both donor and host tissue, with a protective role dominating within GVHD of the lung and pathogenic effects dominating in the gastrointestinal tract. [2][3][4] In addition, the cellular subsets producing IFN␥ and the timing of production may also impact the effect of the cytokine after BM transplantation. 5 In contrast, the role of type I-IFN after BM transplantation remains largely unknown.All type I-IFNs act through the same receptor, which is composed of 2 subunits, IFNAR...

We have quantified the relative contribution of donor antigen-presenting cell populations to alloantigen presentation after bone marrow transplantation (BMT) by using transgenic T cells that can respond to host-derived alloantigen presented within the donor major histocompatibility complex. We also used additional transgenic/knockout donor mice and/or monoclonal antibodies that allowed conditional depletion of conventional dendritic cells (cDCs), plasmacytoid DC (pDCs), macrophages, or B cells. Using these systems, we demonstrate that donor cDCs are the critical population presenting alloantigen after BMT, whereas pDCs and macrophages do not make a significant contribution in isolation. In addition, alloantigen presentation was significantly enhanced in the absence of donor B cells, confirming a regulatory role for these cells early after transplantation. These data have major implications for the design of therapeutic strategies post-BMT, and suggest that cDC depletion and the promotion of B-cell reconstitution may be beneficial tools for the control of alloreactivity. IntroductionRecognition of host alloantigen (alloAg) by donor T cells commonly results in graft-versus-host disease (GVHD), which is a key contributor to the high mortality associated with bone marrow transplantation (BMT). GVHD is initiated by residual host antigen-presenting cells (APCs) that directly present host antigen (Ag) to donor T cells. 1 Subsequent Ag presentation is mediated by donor APCs, which present host Ag to donor T cells via the indirect pathway of antigen presentation, predominantly via major histocompatibility complex (MHC) class II to CD4 T cells. The APC populations contributing to this effect and the rate at which this process occurs after BMT are unclear. Using novel reagents, we demonstrate that donor conventional dendritic cells (cDCs) are the primary APCs responsible for indirect presentation of alloantigen after BMT, and this process commences almost immediately after transplantation. Methods MiceFemale C57BL/6 (B6, H-2 b , CD45.2 ϩ ), B6.Ptprc a (H-2 b , CD45.1 ϩ ), and BALB/c (H-2 d , CD45.2 ϩ ) mice were purchased from the Animal Resource Center (Perth, Australia). B cell-deficient (B6.MT; H-2 b , CD45.2 ϩ ) mice were bred at the Queensland Institute of Medical Research (QIMR; Brisbane, Australia). B6.CD11c.DTR transgenic (Tg) mice (where the diphtheria toxiin [DT] receptor and enhanced green fluorescent protein [EGFP] are driven off the CD11c promoter) and congenic BALB/c mice (H-2 d , CD45.1 ϩ ) were bred at the Herston Medical Research Centre (Brisbane, Australia). Macrophage-Fas-induced apoptosis (MAFIA) Tg (B6.MAFIA, H-2 b , CD45.2 ϩ ; where Fas and EGFP are driven off the c-fms promoter) were provided by A.R.P. In the CD11c.DTR mouse, administration of DT leads to systemic depletion of donor cDCs in treated animals, as evidenced by examination of spleen, peripheral/mesenteric lymph nodes, skin, and lung. [2][3][4][5] We have also confirmed cDC depletion in liver (data not shown). In the MAFIA mouse, the sys...