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Donor regulatory T cells rapidly adapt to recipient tissues to control acute graft-versus-host disease [TCR-seq]

ABSTRACT: Adoptive transfer of donor regulatory T cells (Treg) is a promising treatment option for Graft-versus-Host disease (GvHD), but has not yet found its way into routine clinical practice. To map distinctive properties of protective Treg (generated by either polyclonal or allogeneic in vitro expansion), we followed their fate in recipient organs (spleen, liver, colon) in a prophylactic mouse model of MHC-mismatched bone-marrow transplantation (BMT). Using comprehensive gene expression and T cell receptor profiling, we show that both in vitro expansion protocols generated Treg products that preserved hallmark Treg properties, ameliorated GvHD symptoms, retained their phenotypic plasticity and rapidly acquired organ-specific gene expression profiles after BMT, comparable to their tissue-resident counterparts. When co-transplanted with GvHD-inducing T cells, Treg enabled hallmark suppressive and cytotoxic features, most evidently in the colon. Dominant Treg T cell receptor clonotypes were evenly distributed between organs and across recipients, suggesting a major role of ubiquitous alloantigen-specific Treg in controlling GvHD. Effective protection inversely correlated with the relative abundance of organ-specific Treg, that were transcriptionally distinct, less “activated” and preferentially accumulated in the colon of recipients receiving polyclonally expanded Treg. In summary, we provide a detailed atlas of Treg selection and adaptation in the prophylactic therapy of GvHD.

ORGANISM(S): Mus musculus

PROVIDER: GSE223797 | GEO | 2024/01/01

REPOSITORIES: GEO

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Project description:During inflammatory diseases, infiltrating immune cells can induce endothelial activation and angiogenesis by cytokines and other mediators. The inhibition of inflammation-associated angiogenesis ameliorates inflammatory diseases by reducing the recruitment of tissue infiltrating leukocytes. However, there is limited evidence on initial mechanisms of both processes. We show in experimental models that angiogenesis precedes leukocyte infiltration during graft-versus-host disease (GVHD). GVHD, a systemic inflammatory disease caused by host-reactive T cells primarily attacking the epithelial cells of the GVHD target organs liver, skin and intestines, leads to substantial morbidity and mortality after allogeneic hematopoetic stem cell transplantation. A key feature of GVHD is the incompletely understood organ tropism to skin, liver and the intestines. We demonstrate that angiogenesis initiates GVHD in target organs whereas in non-target organs no angiogenesis and no subsequent inflammation occurred. To shed light into the initiation phase of angiogenesis we looked at classical endothelial cell activation signs, such as upregulation of the Vegfa/VEGFR1+2 pathway or adhesion molecules, but could not find an association. However, endothelial cells in early GVHD showed profoundly higher deformation in real-time deformability cytometry suggesting enhanced migratory and proliferating potential of endothelial cells during the initiation of angiogenesis in GVHD target organs. We used microarrays to detect alternative pathways in endothelial cells of the GVHD target organ colon that could be responisble for initial angiogenesis in GVHD. We identified several up-and down-regulated genes during this process. Strikingly, we found several cytoskeleton as well as metabolic-associated and related gene alterations which may explain the enhanced migration and proliferation of endothelial cells in initiating GVHD. Our study adds evidence to the hypothesis that angiogenesis can initiate inflammation and provides novel insight in pathophysiology and tropism of GVHD.

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Donor regulatory T cells rapidly adapt to recipient tissues to control acute graft-versus-host disease [TCR-seq]

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