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.
Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract is the principal determinant of lethality following allogeneic bone marrow transplantation (BMT). Here, we examined the mechanisms that initiate GVHD, including the relevant antigen-presenting cells. MHC class II was expressed on intestinal epithelial cells (IECs) within the ileum at steady state but was absent from the IECs of germ-free mice. IEC-specific deletion of MHC class II prevented the initiation of lethal GVHD in the GI tract. MHC class II expression on IECs was absent from mice deficient in the TLR adaptors MyD88 and TRIF and required IFNg secretion by lamina propria lymphocytes. IFNg responses are characteristically driven by IL-12 secretion from myeloid cells. Antibiotic-mediated depletion of the microbiota inhibited IL-12/23p40 production by ileal macrophages. IL-12/23p40 neutralization prevented MHC class II upregulation on IECs and initiation of lethal GVHD in the GI tract. Thus, MHC class II expression by IECs in the ileum initiates lethal GVHD, and blockade of IL-12/23p40 may represent a readily translatable therapeutic strategy.
FoxP3 ؉ confers suppressive properties and is confined to regulatory T cells (T reg ) that potently inhibit autoreactive immune responses. In the transplant setting, natural CD4 ؉ T reg are critical in controlling alloreactivity and the establishment of tolerance. We now identify an important CD8 ؉ population of FoxP3 ؉ T reg that convert from CD8 ؉ conventional donor T cells after allogeneic but not syngeneic bone marrow transplantation. These CD8 ؉ T reg undergo conversion in the mesenteric lymph nodes under the influence of recipient dendritic cells and TGF-. Importantly, this population is as important for protection from GVHD as the well-studied natural CD4 ؉ FoxP3 ؉ population and is more potent in exerting class I-restricted and antigen-specific suppression in vitro and in vivo. Critically, CD8 ؉ FoxP3 ؉ T reg are exquisitely sensitive to inhibition by cyclosporine but can be massively and specifically expanded in vivo to prevent GVHD by coadministering rapamycin and IL-2 antibody complexes. CD8 ؉ FoxP3 ؉ T reg thus represent a new regulatory population with considerable potential to preferentially subvert MHC class I-restricted T-cell responses after bone marrow transplantation. (Blood. 2012;119(24): 5898-5908) IntroductionThe development of GVHD remains a major limitation to the therapeutic potential of bone marrow transplantation (BMT). GVHD occurs as a result of immunologic damage to the host tissue by conventional T and NK cells in the transplanted donor graft. Natural regulatory T cells (T reg ) are defined by the expression of FoxP3 1 and are dedicated to suppression of immune responses. The importance of CD4 ϩ FoxP3 ϩ T reg in peripheral tolerance is well established, and the presence of naturally occurring CD4 ϩ T reg makes them an attractive target for adoptive transfer to control pathologic immune responses. Consequently, studies in GVHD using freshly isolated or ex vivo expanded donor CD4 ϩ T reg have demonstrated a delay or prevention of GVHD. [2][3][4][5] Conversely, depletion of CD4 ϩ T reg from the donor graft results in an increased severity of GVHD. 2 A limitation to using naive T reg in the adoptive transfer setting is the high ratio required compared with FoxP3 Ϫ cells in the ingoing graft (1:1); thus, the number of T reg required is restrictive. This has resulted in difficulties transferring adoptive cell therapy into the clinic with multiple groups now focusing on ex vivo expansion protocols in an endeavor to overcome this limitation. [6][7][8] In contrast to the extensive research being completed on naive CD4 ϩ T reg , studies investigating the role of T reg undergoing conversion in the periphery after BMT are lacking. The identification of FoxP3 as a T reg marker 1 and subsequent development of reagents that allow for identification (B6.FoxP3-GFP), 9 tracking (B6.FoxP3.LuciDTR) 10 and depletion (B6.DEREG) 11 of these cells has allowed for a more thorough investigation. We have used these reagents to characterize T reg populations after transplantation with the aim of identifying m...
Mucosal-associated invariant T (MAIT) cells are a unique innate-like T cell subset that responds to a wide array of bacteria and yeast through recognition of riboflavin metabolites presented by the MHC class I-like molecule MR1. Here, we demonstrate using MR1 tetramers that recipient MAIT cells are present in small but definable numbers in graft-versus-host disease (GVHD) target organs and protect from acute GVHD in the colon following bone marrow transplantation (BMT). Consistent with their preferential juxtaposition to microbial signals in the colon, recipient MAIT cells generate large amounts of IL-17A, promote gastrointestinal tract integrity, and limit the donor alloantigen presentation that in turn drives donor Th1 and Th17 expansion specifically in the colon after BMT. Allogeneic BMT recipients deficient in IL-17A also develop accelerated GVHD, suggesting MAIT cells likely regulate GVHD, at least in part, by the generation of this cytokine. Indeed, analysis of stool microbiota and colon tissue from IL-17A-/- and MR1-/- mice identified analogous shifts in microbiome operational taxonomic units (OTU) and mediators of barrier integrity that appear to represent pathways controlled by similar, IL-17A-dependent mechanisms. Thus, MAIT cells act to control barrier function to attenuate pathogenic T cell responses in the colon and, given their very high frequency in humans, likely represent an important population in clinical BMT.
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